Could eating less be the key to living longer? CR-induced LCA activates energy pathways that fight aging and boost health- here’s how!

Calorie restriction (CR) is a dietary strategy that causes a variety of metabolic alterations. CR-induced lithocholic acid (LCA) generation has been linked to increased life expectancy and a variety of other health advantages. A recent Nature study employed metabolomics to look into how CR causes metabolic changes that have physiological benefits (1).

How Does Calorie Restriction Influence Aging?

CR is a non-pharmacological dietary intervention that causes multiple metabolic changes, including changes in cholesterol, free fatty acid, short-chain organic acid, and vitamin levels. CR has been linked to longer lifespans and better health in a variety of taxa, including yeast, mice, flies, nematodes, and primates.

Changes in blood metabolite levels can help to prevent age-related disorders such as protein homeostasis, oxidative damage, and inflammation. Randomized clinical trials have shown that CR reduces age-related frailty and illness, including insulin resistance, central obesity, dyslipidemia, and muscle degeneration.

CR turns on adenosine monophosphate (AMP)-activated protein kinase (AMPK), an enzyme that helps cells maintain energy balance. AMPK controls signaling pathways that postpone aging, including FOXO proteins and TORC1. AMPK also stimulates the formation of nicotinamide adenine dinucleotide (NAD+), which activates transcription factor EB (TFEB), sirtuins, and inhibits CREB-regulated transcriptional coactivators.

AMPK is linked to numerous anti-aging biological processes, including proteostasis, mitochondrial biogenesis, autophagy, mitohormesis, inflammation, and neurodegeneration. As a result, AMPK plays an important role in mediating the health advantages of CR.

Metformin and resveratrol are two CR mimetics (CRMs) that activate AMPK and lead to a longer lifespan in many organisms. Thus, it is critical to understand how CR-mediated metabolic changes in the body activate AMPK to promote good health and longevity.

How Calorie Restriction Impacts Health

This study explored how changes in blood components caused by eating less (caloric restriction or CR) can improve health at both the cell and body levels. Researchers tested this idea by measuring blood and tissue samples from animals like mice, flies, and worms. They found:

Blood from CR Mice Activates a Key Energy Sensor

Blood from mice on a CR diet activated a protein called AMPK, which helps manage energy use in cells. This was observed in various cell types and tissues. Blood from CR-treated mice also contained small, heat-stable molecules responsible for activating AMPK.

Unique Changes in CR Blood

Blood samples were analyzed, and 695 molecules were found to change due to CR. Key differences included lower levels of phenylalanine, long-chain fatty acids, and tyrosine, but higher levels of short-chain fatty acids, bile acids, and acyl-carnitine.

Discovery of LCA

Among these molecules, a compound called lithocholic acid (LCA) was identified as a strong AMPK activator. It works even at very low levels and does not interfere with normal energy production. LCA’s effects were specific to CR and did not depend on other bile acids.

Benefits of LCA in Aging

Giving LCA to older mice improved their muscle strength and endurance. Their muscles recovered faster after injuries, and their overall physical performance, like running and grip strength, got better. LCA also helped reduce problems like glucose intolerance and insulin resistance that come with aging.

In simple terms, eating less triggers changes in the blood that activate key health-boosting processes. Among these changes, LCA stands out as a powerful molecule that improves energy use, muscle health, and overall fitness, especially in older animals.

LCA has been found as a CR-induced metabolite capable of activating AMPK and increasing the lifespan of several organisms, including hermaphroditic worms, flies, and mice. Thus, LCA’s anti-aging properties were demonstrated.

References:

1. Lithocholic acid phenocopies anti-ageing effects of calorie restriction
   (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)

Source-Medindia