A Bile Acid that Increases Longevity and Improves Muscle - New Research

New research in Nature has identified a bile acid called Lithocholic Acid (LCA) that could be the missing link between caloric restriction and improvements in lifespan and health span.

New research in Nature has identified a bile acid called Lithocholic Acid (LCA) that could be the missing link between caloric restriction and improvements in lifespan and health span. We will break down the science behind this discovery, explore how it impacts muscle performance, metabolism, and longevity.

**There’s now a video cover these data. For those who prefer to watch, click below.**

Brief Background

For background, caloric restriction has been shown repeatedly in lower organisms, like fruit flies and worms to extend lifespan.

In mammals, the effects tend to be smaller in terms of lifespan; however, can still be sizable with respect to healthspan, which one could argue is at least equally important.

But the cascade of mechanisms linking caloric restriction to lifespan and healthspan has remained murky.

And we need to consider serious tradeoffs in humans. In particular, low-calorie diets can lead to muscle loss and frailty, which is a serious problem. We will hit on that below, with some very exciting muscle-centric findings.

New Study: Healthspan Results

Okay, what did the research do and what did they find?

Well, first they subjected mice to calorie-restricted diets for 4 months and looked in their blood for metabolites that stood out as distinct from control mice.

The initially identified 695 metabolites that were significantly altered, and then looked for those that activated proteins known to be involved in “anti-aging” and could be transferred to control mice to replicate the health benefits of calorie-restriction.

One stood out, a bile acid called Lithocholic acid (LCA).

Figure 2B. LCA concentration (red) in calorically restricted mice across the day, as compared to ad libitum fed control mice (green).

LCA is a secondary bile acid made by gut bacteria in both mice and humans, and has similar concentrations in both mice in humans.

(Nuance Note: Since bile acid metabolism in mice and humans does have differences, the researchers generated “bile acid humanized mice” that more closely replicated the bile acid profile of humans, and LCA concentrations remained similar between the squeakers and naked big-brained apes. That’s a way of building a case towards the ultimate findings having relevance in humans. But more on that momentarily.)

They then went on to see what benefits feeding LCA directly to mice has on their physiology, and found that LCA:

• lowered blood glucose

• increased GLP-1 levels

• improved various aspects of muscle performance

• increased the number of oxidative fibers

• improved grip strength

• increased running distance

• increased mitochondrial content

• increased muscle regeneration after damage by activating muscle stem cells

The benefits on muscle are notable, particularly because normal caloric restriction can lead to muscle wasting, as can GLP-1 receptor agonists for that matter. But LCA appears to benefit muscles, meaning the benefits of caloric restriction without one major potential downside.

Lifespan Results

They then went on to see what the effects are on lifespan, staring with flies and worms, and found significant 23% (left) and 11% (right) increases in median lifespan in worms and flies, respectively.

Figure 4A, B.I simplified the diagram, but for those wanting to know, the green and red line are wildtype animals, with green being control and red being LCA treatment. The other lines (blue and brown) have the genes coding for AMPK knocked out. This helps to demonstrate the essential role of the enzyme, AMPK, in mediating the effect of LCA on lifespan.

In mice, there was a consistent positive trend towards increasing lifespan, 5% in male mice and 10% in female mice, although the finding fell short of statistical significance.

Figure 4G. Effect of LCA on lifespan in mice. Three cohorts of ad libitum-fed male and female wildtype mice were fed LCA at 1 g/l starting at 1 year of age of age.

To simplify this, I interpret the consistency of the trend in different mouse cohorts as suggesting the lifespan effect was smaller in the little mammals, although there was still a signal… and 5-10% is nothing to sneeze at.

Human Relevance

I’d expect, in humans, the actual years of life gained from LCA supplementation wouldn’t be many, if any, but that doesn’t detract from the benefits on healthspan.

This is generally a rule of thumb for “anti-aging” compounds in humans – typically the effects on lifespan are thought to be minimal, although the effects on healthspan may be sizable. Honestly, I care more about the latter anyway.

Now, more on LCA in humans.

Interestingly LCA is one compound that’s increased in humans after 36 hours of fasting, and high levels of LCA are found in centenarians who also harbor high levels of gut bacteria that make LCA.

And, mechanistically, LCA operates by activating AMPK – which is likewise activated by fasting and also low-carbohydrate ketogenic diets, which have both been proposed as caloric-restriction mimicking diets and which both change bile acid metabolism, with reported metabolic health benefits.

So, what does this mean?

1. Better understanding of the metabolic effects of caloric restriction allows to potentially co-opt systems coded into our DNA (and microbiomes) by evolution to extract benefits without actually needing to go on low-calorie diets.

2. Dietary manipulations – like fasting or carbohydrate restriction – can, through calorie-independent mechanisms, like bile acid manipulation, have extreme effects on health.

In summary, the discovery of LCA as a potential mediator of the benefits of caloric restriction is an exciting step forward in understanding the link between diet, gut health, and longevity.

While its direct impact on lifespan in humans may be modest, the profound healthspan improvements—particularly for muscle performance and metabolic health—make it a promising area for further research.