My White Whale

The big bug that might let you live to 120.

Elon Musk has a line: “The most entertaining outcome is the most likely.”

I like this saying, because it aligns well with the notion that the cure to a lot of modern man’s woes is literally shit—that the answer has in fact been inside us all along, and we’ve been flushing it down the toilet.

So I am particularly entertained by the results of a study which came out this year, reporting some distinct microbial features in the guts of centenarians—people who have managed to live to well over 100.

Naturally, this kind of thing is interesting to a lot of people. The quest for the fountain of youth is as old as time, but in the past few years there’s been a huge boom in the science of life extension, with the upshot that billionaires are doing things like (allegedly) getting blood transfusions from young people, to try and squeeze a few extra years out of life. But imagine: what if all that creepy vampire stuff has been for nothing? What if it turns out that, this whole time, the secret to long life has been as simple as eating a turd from a guy who’s 120 years old—but doesn’t look a day over 98?

That’s entertainment.

“Musk’s maxim” isn’t the only reason to think this might be the case. The microbiome is as promising a place as any to look for the secret to long-term health: it’s the greatest source of functional genetic diversity among humans, and a lot easier to modulate than the genome.

The Boring Part: Nature’s Cancer Vaccine

Some aspects of the study’s findings weren’t too surprising: for example, young people and the healthy-centenarian cohorts both had higher levels of certain kinds of Bacteroides. This is the predominant genus in most healthy people’s guts, and its members play a lot of important roles in the microbiome.

Metabolically, Bacteroides are the Swiss-army-knife of gut bacteria, with a rich and diverse arsenal of enzymes for breaking down complex carbohydrates and proteins. They’re also master regulators of the immune response, controlling the production of antibodies like IgA—the body’s first line of defense against pathogens.

But Bacteroides is a big genus. The same way that oak trees are found on every continent in a million varieties, from red to Spanish to Garry, there are a lot of different kinds of Bacteroides out there, each with unique features adapted to its ecological niche and strategy—and not all of them are necessarily friendly. The same toolkit that lets Bacteroides manipulate the immune system to our benefit can also be used to evade or subvert it, so it’s only natural that some species would be better than others for maintaining the right balance of pro- and anti-inflammatory activity that sets the stage for healthy longevity.

Consider the case of the Thomsen-Friedenreich (or “TF”) antigen. This is a molecule that’s found on the outside of most of your cells, but ordinarily in a “masked” or hidden state. But something about the transformation from a healthy cell to a cancer cell causes the TF antigen to become exposed, or “unmasked”. This is part of how the immune system recognizes and fights cancer: circulating antibodies stick to the unmasked TF antigen on tumor cells, which flags them for destruction.

But you also find TF antigen on the surface of certain gut bacteria, including Bacteroides species. This isn’t a coincidence—the presence of these TF-expressing bacteria in the gut seems to be what drives the body to produce the anti-TF antibodies in the first place…meaning that the abundance of these bacteria in your gut is probably a major determinant of your immune system’s level of passive alertness against any budding tumors.

This makes sense in the context of the notion of vaccines and adjuvants. Many vaccines work by giving the immune system a “training” sample of the pathogen you want to protect someone against, along with an adjuvant—an irritant molecule that provokes an aggressive local immune response. The adjuvant helps the immune system learn that the pathogen’s cellular structures mean bad news, almost like Pavlovian conditioning. Because some Bacteroides express both TF antigen and pro-inflammatory molecules on their surfaces, they’re like nature gave us a 2-in-1, vaccine and adjuvant system, tailor-made to help the body fight cancer.

All this to say: I’m not surprised that having the right Bacteroides in your gut is one of the strongest correlates with insane longevity. So let’s not talk about that bit anymore, because there was one thing in this paper that really did surprise me.

Big if True

One of the neat findings from this study is that, just by looking at the bacteria in a turd, you can tell pretty reliably whether the person that turd came from is a centenarian or not, using a sort of flowchart based on the relative abundances of various species.

I’m not a data scientist, so I’d probably butcher the description of how those flowcharts are constructed, but the upshot is that if you were looking at a random poop from this study and trying to figure out whether or not it came from a centenarian, there’s one single piece of information that’s more important than all the rest. That is: if you tried to build your flowchart without including this info, it would result in more misclassifications than dropping any other piece of information.

It is the abundance of a genus called Epulopiscium, which happens to be found more often in the guts of centenarians.

All the rest of those names near the top of the list, they’re pretty standard parts of a human microbiome. Staphylococcus is one of the most abundant microbes on human skin. Escherichia-Shigella is the genus that contains E. coli. And in my time doing anaerobic cultivation, I’ve bagged dozens of Odoribacter, Faecalibacterium, Eggerthella, and Alistipes from the human gut.

But Epulopiscium…that’s a name I have not heard in a long time.

The only time I’ve seen it before was back in 2016 or so, in my read through of Ed Yong’s I Contain Multitudes—a pop-sci primer on the microbial world which came out right as the field of microbiome science was really starting to pop off. It’s a great book; Yong takes less of a hard focus on the human body than I do, looking instead at the exotic edge cases that illustrate the fascinating variety of symbiotic evolutionary strategies that bacteria have developed: things like bioluminescent bacteria that help camouflage their hosts in moonlit seas.

Epulopiscium well deserves its place in Yong’s flea circus of exotic microbes; it’s one of the most interesting bacteria out there. For starters, it’s among the largest bacteria on Earth.

How large? If you had one on your screen, you’d probably go ew and try to wipe it away—they’re visible to the naked eye, measuring up to 0.7mm long.

That’s a Pseudomonas, but whatever.

Now, I have written before about the importance of magical thinking—about listening to the voice in your gut which says “this must mean something”, even if you don’t know exactly what, or how.

So what does it mean that one of the largest bacteria known to man is unusually abundant in the guts of the longest-lived people?

Fish Guts

For one thing, it probably means they’re eating fish gut soup.

See, Epulopiscium is native to the guts of surgeonfish, a broad group which includes species like the blue tang (think Dory from Finding Nemo) as well as some extremely goofy-looking guys, like the genus Naso—also known as the unicorn fish.

It’s not the unicorn we want, but it’s the unicorn we deserve. Image Credit: Jens Petersen, (CC-BY 2.5)

Surgeonfish are native to the coral reefs of tropical waters, and this study was conducted in the Guangxi region on the coast of the South China Sea…so right off the bat, it seems likely that this is a local effect which wouldn’t have shown up if the study had been conducted somewhere like Germany.

But just because it’s local doesn’t mean it’s not important: if you’re hunting for the fountain of youth—even within the human body—you might only find it in a certain enclave.

So what could be going on here, biologically?

The least optimistic possibility is that we’re simply seeing transient microbes: maybe centenarians in Guangxi are eating fish gut soup often enough that the fish’s gut bacteria are showing up in their poop. This seems plausible; the centenarians might be the only people in the study population who still make their fish soup the really old-fashioned way. Maybe Epulopiscium is simply a marker of a very-high-fish diet, and the fish is what drives longevity, thanks to (boring) things like its high concentration of omega-3 fatty acids.

But the more intriguing possibility is that a species of bacterium which ordinarily lives in the surgeonfish gut has genuinely made the jump to the human GI tract, and has engrafted: becoming an active part of these people’s microbiomes, eating what they eat, reproducing inside them…and somehow conferring their newfound hosts with an almost-supernaturally long life. In theory, there’s no reason why that kind of engraftment across species couldn’t happen; the conditions of the surgeonfish gut are decently similar to the human gut, and Epulo is a spore-former, meaning it can survive things like cooking and stomach acid.¹

This is the most optimistic model. If it’s the correct one, there’s a possibility that the longevity associated with the presence of Epulopiscium is a transferable phenotype. Maybe a good fish soup can be really, really good for you.

How, though? Why? Could it be as simple as “gut bacteria = good”, therefore “very big gut bacteria” = “very good”?

Silly as it sounds, I wouldn’t rule it out. Maybe there are some square-cube law economies of scale going on, where the 100x difference in length between a Bacteroides and an Epulopiscium makes the latter 10,000x more efficient at producing short-chain fatty acids or something.

But if there's something real going on here, it’s probably not so simple. Epulos are deeply, deeply weird organisms: While nearly every other bacterium reproduces by splitting into two identical cells, Epulo essentially gives birth to a litter of live young, dying in the process. Where most microbes have one copy of their genome per cell, Epulos have hundreds of thousands. God only knows what other tricks they’ve got up their sleeves.

Part of the reason we know so little about their biology—what kind of chemicals and proteins they produce—is because nobody has ever grown one in culture. We simply haven’t figured out what they eat yet, or what weird environmental conditions they need in order to feel at home. This is a common problem in microbiology: a lot of the most interesting bacteria in the human gut, like the ones most strongly anti-correlated with depression severity, stubbornly refuse to grow in isolation. Wherever you see names like the “UCG_003” and “UCG_004” on the list above, you’re seeing bacteria that plenty of people have inside them, but nobody’s yet been able to grow in a test tube.

With some “uncultivable” bugs, like the one that causes leprosy, we can at least study them in their animal hosts: you can’t grow Mycobacterium leprae on a petri dish, but you can infect an armadillo with it and keep the armadillo in a cage. But if you catch a surgeonfish and put it in a tank, all the Epulos disappear from its gut within a couple of days.

If these mysterious bugs do hold the secret to long life, they’re not giving it up without a fight.

The Hunt

It’s fitting that a finding like this should be tantalizing, like sighting an actual whale at sea: a brief burst of mist on the horizon, the glimpse of a colossal tail slapping down—and then it’s gone as the water closes over it.²

Given time and money, we could hunt it down. We could try and replicate the finding, find people from the same region who have Epulos in their stool, learn about their diets. Tell them not to eat any fish for a week and see if the signal goes away, which would indicate that the organism isn’t engrafted. Maybe in the process, we’d learn something about what it takes to grow these bacteria in culture; if the bacterium has engrafted, then either something in these people’s diets or something in their microbiomes is feeding it.

Maybe, like a lot of other megafauna, it only thrives when there’s a flourishing ecosystem to support it. It’s a funny thing that whales, some of the largest animals ever to grace the Earth, survive by eating some of the smallest, i.e. krill. Maybe “As above, so below” holds true here, and Epulopiscium survives by eating the smallest denizens of the microbiome, bacteriophages.³

But it might not be that complicated. Maybe it just needs some kind of seaweed, or chitin (the tough carbohydrate found in both mushrooms and crustaceans) to survive. Maybe it needs phytoplankton, or a load of iodine, or any of the million other things you find in seawater but not in your average bacterial cultivation medium. Maybe its spores just aren’t as hardy as those of other bacteria, and it needs to go straight from its home in the fish’s gut to another anaerobic environment—like a hot pot of soup, or a human GI tract. Most of the time when a microbe is considered uncultivable, it’s because nobody’s really dedicated a lot of effort and creativity to cultivating it.

So this is my white whale. It might be a fool's errand or an artifact in the data, but I've spotted this great big something in the distance, and marked it on my map with a note: Someday. When I have the time to chase something that might turn out to be a mirage.

For now, I’ve got my hands full hunting more conventional fare: Last week, I arrived in Switzerland—a little town called Davos—to set up an anaerobic cultivation lab at the behest of my company. For the next year, I’ll be isolating human gut anaerobes here, wrangling bacteria…playing Pokémon with poop.

Some will be easy; microbes that anyone with an anaerobic chamber can nab using standard techniques, like those Bacteroides, or Coprococcus. Even these common bacteria can be powerful, though—if I do my job right, in a few years you might have a probiotic in your hands that can reduce your risk of cancer, or improve your motivation to exercise. But I’ll also have the chance to hunt for some of the more elusive ones, things that I’ve written about here before: as-yet-uncultivated bacteria like cholesterol-reducers, or those UCGs. Lowering people’s cholesterol sounds boring, but if you’re interested in saving lives, it’s the kind of target to shoot for.

But one day, I hope I’ll have the chance to find out firsthand what’s going on with this macroscopic microbe—to go to Guangxi, or the islands of Indonesia. To dive, like Gilgamesh, to the bottom of the sea in search of the secret to long life. To spear a unicorn fish, and cut it open, and eat from its innards these strange grains that might be little flecks of immortality. To sequence my shit and see if they live on within me. To bring some back to the lab, and see if I can coax them to life in a test tube. To share them with the world.

But in the meantime…I've got smaller fish to fry.

🖖🏼💩

1. It’s also possible that we’re not even seeing a true Epulopiscium, but a human gut-native species that’s closely related enough to Epulo to get misclassified by the metagenome-assembling algorithms. One of Epulo’s closest documented relatives (the similarly large Metabacterium), is apparently native to the guinea pig GI tract.

2. It’s also fitting, to anyone who’s read the Harry Potter series, that a “unicorn” might just be able to grant long life to anyone who kills and eats it…even if it is the stupid-looking fish version that we have in real life.

3. It’s been estimated that, every 48 hours, half of all bacteria on Earth are killed by bacteriophages. Since every cell killed by phages becomes, in the time before its death, a factory for more bacteriophages, this represents a colossal nutrient sink in any microbiome. Someone’s gotta be eating that—nature doesn’t leave food on the plate—and “virovory” has been demonstrated in ciliates. Ciliates are eukaryotes, but there’s no reason why the right bacteria couldn’t do the same.