It really is stunning how often I see longevity grifts make the news cycle. If the headlines aren’t about living forever by getting to some imaginary “escape velocity”, then they at least give you the hope that you can significantly increase your time here on earth. Millionaires and billionaires have taken to longevity science – and longevity “science” – with the goal of elongating their lifetimes and continuing their domination of the private and, increasingly, public spheres.
With the interests in longevity on the rise, we are bound to see both scientifically promising treatments (by this I mean a realistic and incremental improvement in health outcomes at older ages) and a large helping of pseudoscience, as well as everything in between.
On one hand we have things like tech-bro Bryan Johnson infusing himself with his son’s plasma as a “biohack” to reverse aging – a regime he later stopped, because (surprise, surprise) it didn’t work. On the other hand, we have some scientifically plausible interventions such as epigenetic reprogramming (like Yamanaka factors) or various possible senolytic drugs. Currently, these interventions are still in development and have not been widely implemented in humans, for various reasons. If history is any guide, most of these interventions will quietly be shown to be ineffective, unsafe, or both.
One of the possible useful interventions against ageing is calorie restriction (CR), which has been studied for almost a century for its anti-ageing properties… but the operative word here is “possible.” Research has established that, under laboratory conditions, CR can lead to longer lifespans in organisms such as research worms (C. elegans), flies (D. melanogaster), and mice (M. musculus). Effectiveness, however, is less apparent in primates and people, and there are still many unresolved questions underlying the concept.
One long-standing problem with CR is that very few people would be willing to comply with the protocol. Simply put, it is difficult to eat as little as would be necessary to match a lot of the research done on animals. With unclear or questionable benefits, it turns out to be a big ask. Given this, there has long been an interest in developing some kind of pharmaceutical mimic of CR; something that would provide the benefits of CR without the pesky need to eat like a person on a hunger strike.
There have been a number of proposed molecules to mimic CR over the years, but one that wasn’t on my radar until recently is Lithocholic Acid (LCA). Like many other hopeful CR-mimicking molecules, it has had some interesting metabolic functions and relatively novel research behind it. LCA is not directly synthesised by our bodies. Instead, it is derived from the microbiota of the gut, which is great because I need more ways to worry about whether or not my gut is healthy. The reason LCA is thought to be capable of mimicking CR is in its ability to activate an enzyme known as adenosine monophosphate activated protein kinase – which is a mouthful, so we usually just use the initialism AMPK.
AMPK is a really interesting enzyme, and I’m sure it has taken up a significant amount of the career of dozens or even hundreds of researchers. AMPK has extremely wide ranging and complex metabolic effects, including playing a role in regulating glucose uptake, glycolysis, fatty acid synthesis, cholesterol regulation, protein synthesis, autophagy, sirtuin activation, and more. Obviously, there are dozens – if not hundreds – of downstream effects from AMPK regulation, as it is implicated in all of these metabolic pathways. Further, these same pathways are thought to be affected during times of calorie restriction: LCA levels increase under calorie restriction conditions in some models, and has been proposed as one upstream signal that may contribute to AMPK/sirtuin activation thereby affecting all the downstream metabolites. All of this makes lithocholic acid of great interest for ageing research and a plausible target for pharmaceutical intervention.
Naturally, scientists began looking into LCA. Research has indicated a similar pattern to CR as one might expect: flies and worms improved in various ways and lived longer, consistent with CR research; mammals, however, presented differently. In one December 2024 study, while LCA treatment increased muscle strength, ability to run, and increased mitochondria activity, there was no mention of mice living longer. Given the fact that mice were a subject of the study, it would be odd if they weren’t looking for extended lifespan. My guess, it just wasn’t statistically significant.
There are other reasons we should be skeptical of something like LCA as a treatment for longevity. One of these reasons is the fact that LCA seems to be capable of both promoting tumour formation and suppressing it based on context (concentration and the microenvironment in which it is found), and it may very well be hepatotoxic. All of this is consistent with the pattern of many such hopeful longevity molecules: there is a scientific plausibility for a desirable treatment, a small amount of hype in industry and among researchers, a few headlines come out about another “fountain of youth,” and then nothing comes of it, or it only has niche applications.
As a final note I am happy to say LCA has yet to be picked up by the supplement industry and is only really available for purchase as a laboratory reagent (please don’t ingest reagents). I wouldn’t be surprised if some biohacker or supplement company tries to market it as “SUPER AMPK” at some point, but at least now you’ll know to roll your eyes and pass up their offer.
