Longevity Briefs: A Molecule That Replicates The Benefits Of Calorie Restriction

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Calorie Restriction – a sharp reduction in calorie intake without causing malnutrition – is one of the oldest known ways to extend the lifespan of animals. Calorie restricted mice live as much as 35% longer than their normally feeding peers, though the benefits of calorie restriction seem to diminish in larger mammals, and it’s unclear whether calorie restriction extends human lifespan.

Regardless of whether it extends lifespan, calorie restriction does appear to have many health benefits in humans, such as improved blood sugar control. Calorie restriction works by causing metabolic adaptations to the way in which the body manages its energy. A molecule that could mimic some of these adaptations could be highly beneficial, allowing people to obtain some of the benefits of calorie restriction without actually needing to reduce caloric intake. In this study, researchers use a screening strategy in an attempt to identify such a molecule.

The discovery:

In the study, researchers took serum (the liquid portion of the blood after clotting) from mice that had been fed a calorie restricted diet for 4 months, and found that this serum was able to activate a molecule called AMPK (AMP-activated protein kinase) in both cells and live mice. AMPK is a master regulator of energy metabolism, and is activated when energy supply is low (such as during calorie restriction) in order to bring about appropriate metabolic adaptations.

The researchers then screened molecules within the blood of calorie restricted mice in an attempt to find out which ones were responsible for activating AMPK. They narrowed them down to 6 molecules, only one of which was able to activate AMPK at concentrations similar to those found in the blood. This molecule – a bile acid called lithocholic acid (LCA) that makes fats more soluble for digestion – was then tested in old mice. They found that 1.5 year-old mice given LCA in their drinking water for a month had significantly improved physical performance, including better grip strength and running speed in comparison to control mice. They also didn’t lose any muscle mass, which tends to happen under calorie restriction in both mice and humans.

LCA also significantly extended lifespan in both nematode worms and flies, but not when AMPK was genetically deleted. Finally, researchers gave LCA to three different cohorts of mice starting at 1 year of age. The average (median) lifespan of these mice was generally 8%-10% longer than their untreated counterparts, though these increases weren’t statistically significant.

The implications:

LCA appears to mimic the effects of calorie restriction, resulting in health benefits for aged mice. LCA is common to humans and to mice, and there is already data suggesting that healthy centenarians (people who live to age 100) have higher levels of LCA in their guts, so LCA might have some beneficial effects in humans as well. LCA is produced by gut bacteria – specifically by Lactobacillus, Clostridium and Eubacterium species when they metabolise precursors secreted by the liver. Clostridioides in particular appear to be correlated with LCA levels in older humans, so there may be potential for improving health in old age by targeting these species or otherwise raising LCA levels in humans.