This Gut Molecule Improves Muscle and Boosts Metabolism

What if a molecule made by your gut bacteria could unlock the benefits of caloric restriction, like improved health and longer life, but without cutting calories? New research in Nature has identified a bile acid called lithocholic acid, or LCA for short, that could be the missing link. And in this video, we're going to break down the science behind the discovery. We're going to explore how how LCA can impact muscle performance, metabolism, longevity, and most importantly, we're going to say what this means for you today and potentially what this means for you decades from now. But first, for background, caloric restriction has been shown repeatedly in lower organisms like fruit flies and worms to extend lifespan. And 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. However, the cascade of mechanisms linking caloric restriction to lifespan and healthspan has remained murky. Also, we need to consider serious trade-offs in humans. In particular, low-calorie diets—caloric restriction—can lead to muscle loss and frailty, which is a serious problem that you don't want, especially in older age. We're gonna hit on that very point in this video with some super exciting muscle-centric findings. Okay, now what did the researchers do and what did they find? Well, first they subjected mice to caloric-restricted diets for 4 months and then looked in their blood for metabolites that stood out as distinct from control mice.. And in their initial screening, they identified 695 metabolites that were significantly altered by caloric restriction. And then they looked for those that activated proteins known to be involved in anti-aging pathways, like AMPK, and those that could be transferred to control mice to replicate the health and benefits of caloric restriction. And one molecule in particular stood out. This bile acid, lithocholic acid, or LCA. LCA is a secondary bile acid made by gut bacteria in both mice and humans, and actually has similar concentrations in both mice and humans, which is important. And as a quick aside, but a really important one, since bile acid metabolism in mice and humans does have differences, one thing they did in this research study that was really cool is they generated bile acid humanized mice through genetic manipulation that more closely replicated the bile acid profiles of humans. And what they found were LCA concentrations remained similar between the little squeakers and the naked big-brained apes— us. You can tell I'm trying to be creative there. Anyway, that's a way the researchers started to build a case towards the ultimate findings having relevance in humans. But more on that a little bit later, because I do have more to say on humans. They then went on to see what the benefits of feeding LCA to mice directly had on their physiology and found, astonishingly, LCA lowered blood glucose and also increased GLP-1 levels, improved various aspects of muscle performance, including increasing the number of oxidative fibers, improving grip strength, increasing running distance, and increasing mitochondrial content in the muscles. And improving muscle regeneration and recovery by activating muscle stem cells. How cool is that? And the benefits on muscles are particularly notable because normal caloric restriction—low-calorie diets—can lead to muscle wasting, as for that matter can GLP-1 receptor agonists. Remember, LCA also increased GLP-1. But LCA appears to benefit muscles, meaning potentially benefits of caloric restriction without the one, the major potential downside of caloric restriction, this muscle wasting. LCA helps muscles instead. Anyway, the researchers then went on to see what the effects were on lifespan, starting in flies and worms, and found a significant 11% increase in fly median lifespan and 23% increase in worm median lifespan. Now, they did this experiment in mice as well to see what the effects were on longevity, and they found a consistent positive trend —with a 5% increase in male mice and a 10% increase in female mice, although these findings did fall short of statistical significance, which may be because they just didn't have enough mice. But 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. A 5-10% increase is nothing to sneeze at. And I expect in humans, the actual years of life gained from LCA supplementation wouldn't be many, if any, admittedly, but that doesn't detract from the benefits on healthspan. And this is generally a rule of thumb for anti-aging compounds in humans. Typically, the effects on lifespan are thought to be minimal as you go from mice to humans, although the effects on healthspan may still be sizable. Now, this is really hard to suss out because it's hard to do these trials in humans. You can't really do an LCA randomized controlled trial in humans for lifespan. But honestly, I care more about the healthspan anyway. Anyway, more on humans now. LCA in humans. Interestingly, LCA is one of the compounds that's increased in humans after about 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, an enzyme which is likewise activated by fasting and low-carbohydrate ketogenic diets, which have both been proposed as caloric restriction mimicking diets, including in this paper by the authors, and which both also change bile acid metabolism with prior reported metabolic health benefits. So, pause for a moment and imagine being able to tap into the same pathways activated in human centenarians by just tweaking your macronutrient intake, cutting carbs really low, or altering your eating windows and implementing intermittent fasting. Isn't that kind of interesting and provocative and hopeful? But what does all this mean? First, I want to make the broad point that better understanding of the metabolic effects of caloric restriction allows us as innovative humans to potentially co-opt systems coded into our DNA and our microbiomes by evolution to extract benefits without actually needing to go on low-calorie diets. Thank goodness. Second, dietary manipulations like fasting or carbohydrate restriction can, through calorie-independent mechanisms like bile acid manipulation, have extreme effects—positive effects—on health. Consider fasting or trying a ketogenic diet if you want and haven't tried before, or other strategies that may naturally increase LCA levels. And if you're fascinated by the intersection of diet, gut health, and longevity, as I am, check out my many other videos on this topic. And let's continue to have this conversation, including in the comments. Tell me, how do these data affect your mindset? Are you going to try to implement them in your own routine? And if so, how? But in summary, The discovery of LCA as a potential mediator of the benefits of caloric restriction is a really exciting step forward in understanding the link between diet, gut health, and longevity. And while its direct impacts on lifespan in humans may be modest, if any, the profound potential benefits on healthspan improvements, particularly in muscle performance, while also mimicking the benefits of caloric restriction, and the benefits on metabolic health make it a really promising area for future research. This work highlights how we might harness natural compounds and dietary strategies, like fasting or keto, to unlock evolutionary pathways for better health, but without extreme calorie cuts. So in summary, the future of longevity science may be about working smarter, not harder, with what our biology already offers. With that, stay curious, and I'll see you in the next one.