Most of the worms in Meng Wang’s lab die on schedule. They live their brief lives on Petri dishes, and after two to three weeks, they die of old age. But some individuals beat the odds, surviving for several days longer than usual.These wormy Methuselahs were all genetically identical, so it wasn’t their genes that explained their decelerated aging. Instead, the secret to their longevity lay in the microbes within their gut.
Wang had loaded all the worms with the same bacterium—a single strain of the common gut microbe E. coli. But in some of these strains, she had deleted a single gene. That tiny change made all the difference, extending the worm’s lives.
This is part of a growing number of studies showing that an animal’s microbiome—the community of microbes that shares its body—can influence its lifespan. And while such research is a long way from developing life-extending probiotics for humans, it points to new leads for ensuring that people stay healthy for as long as possible. “I’ve always studied the molecular genetics of aging,” says Wang, who is based at the Baylor College of Medicine. “But before, we always looked at the host. This is my first attempt to understand the bacteria’s side.”
The connection between microbes and lifespan dates back to Elie Metchnikoff—an eccentric Russian Nobel laureate who the microbiologist Paul de Kruif once described as a “hysterical character out of one of Dostoevsky’s novels.” He believed that intestinal microbes produced toxins that caused illness, senility, and aging, and were “the principal cause of the short duration of human life”. (His claim, though baseless, apparently started a fashion for colostomy in the early 20th century.) On the other hand, he also thought that some microbes could prolong life by producing lactic acid, which killed their harmful cousins. That was why, Metchnikoff believed, Bulgarian peasants who regularly drank sour milk would often become centenarians.
In 1908, Metchnikoff wrote about his ideas in a book called The Prolongation of Life: Optimistic Studies—an ironic title given that the man was a profound pessimist who had twice tried to kill himself. Still, he also quite literally put his money where his mouth was by regularly drinking sour milk, and created a fad that would culminate in the modern probiotics industry. Metchnikoff died at the age of 71, and his claims haven’t quite stood the test of time. But more recently, several groups of scientists have shown that animal microbiomes can indeed influence the lifespans of their hosts.
In 2013, Filipe Cabreiro showed that metformin—a drug that’s used to treat type 2 diabetes, and that’s being investigated for anti-aging properties—lengthens the lives of nematode worms, but only if the worms have microbes in their guts. More recently, Dario Valenzano showed that the killifish—an extremely short-lived fish that’s being increasingly used in studies of aging—lives longer if old individuals consume the poop of younger ones, suggesting either that old microbiomes quicken the deaths of these fish, or that young microbiomes can prolong their lives.
Despite these promising hints, it’s hard to work out exactly why and how the microbiome influences the pace of aging, because these communities can be bewilderingly complex. When you have a huge range of microbe species exchanging an even wider range of chemicals, it’s hard to tell which particular bug or molecule is important.
So Wang decided to sweep that complexity aside and focus on a very simple partnership. Her team member Bing Han started with a library of E. coli strains that were each missing a single gene, but were otherwise identical. He then fed these strains to the nematode C. elegans—a small transparent worm that features heavily in aging research, and whose body and genes have been thoroughly characterized.
Of the 4,000 or so E. coli strains, Han found that 29 extended the worms’ lives by at least 10 percent. And 19 of these “also protected the worms from age-associated diseases” like cancer and neurodegenerative conditions, says Wang. “They lived longer and better.”
Several of these life-extending bacterial strains behaved predictably—they influenced networks of worm genes that are already known to influence the aging process. But two strains did something unexpected. Their missing genes are involved in making colanic acid—a type of sugar found on the surface of many gut microbes. And these particular microbes, because of their deleted genes, were producing unusually large amounts of colanic acid. And when Han stopped them from doing so, they no longer extended the worms’ lives. Colanic acid was the key.
“I think it’s a brilliant story,” says Dario Valenzano, the geneticist behind the killifish study. He was initially concerned that colanic acid was only coincidentally making the worms live longer—perhaps it just stops E. coli from becoming infectious and killing the worms early. But Wang’s team allayed his concerns by showing that the molecule alone could increase the worms’ lifespans, even in the absence of any microbes. “I’m really convinced,” Valenzano adds.
The team also found some hints about how colanic acid works. Very few people have studied this molecule, but it seems to affect the worm’s mitochondria—bean-shaped structures that live inside animal cells and provide them with energy. Colanic acid stimulates these tiny power plants to split apart, making extra copies of themselves. It also switches on a group of genes that help mitochondria deal with stressful conditions, and that have been previously linked to longer life in worms. For reasons that are still unclear, these actions seem to put more sand in the worms’ hourglasses.
Mitochondria are former microbes themselves. They descend from a free-living bacterium that found its way into another microbe and stayed there, becoming a permanent source of energy for the host. That event happened billions of years ago, but mitochondria still retain traces of their former lives as bacteria. And it’s clear that modern bacteria can influence them. “It’s just amazing to me that after so many years of separation, they can still talk to each other,” Wang says.
“It’s a beautiful study, and a fantastic example of how doing basic research in a simple organism can reveal a lot of important findings,” says Siu Sylvia Lee from Cornell University. “It provides one clear mechanism for researchers studying the much more complex relationship between human microbiomes and longevity to investigate.”
For Wang, the ultimate goal is to develop genetically engineered strains of bacteria that can improve human health—a souped-up, life-extending probiotic for modern-day Metchnikoffs to quaff. But that won’t be easy. Despite a lot of research and development, existing probiotics are largely underwhelming, because it is very hard to get these bacteria to stably colonize the gut. “That’s a challenge for the entire field, and we’re collaborating with others to find different ways around it,” says Wang.
A different option would be to find microbe-made chemicals like colanic acid that could have anti-aging effects on their own. “Making people live longer and healthier is very different from treating diseases,” explains Wang. “If I talk to a patient and say I have a magic drug that can cure their disease but has side effects, I think they’d take it. But if you tell a healthy person that you have a compound that would extend their life by five years, but has side effects we don’t know about… I would be hesitant. That’s why I’m looking to the microbiome. Maybe we can find natural compounds that come from the microbes that we can use to boost our health. They’d be safe because they’re already there.”
Obviously, it’s still unclear if her discoveries apply to people, but there’s a reasonable chance that they would. The C. elegans worm—a millimeter long, transparent, and comprising just a thousand or so cells—is obviously very different from us, but its biology is also surprisingly similar. Many of the things that are known to slow aging in animals like primates or mice also work in the worm, from cutting down on calories to taking drugs like metformin and rapamycin. “It’s relevant to us all,” says Jennifer Tullet, who studies aging at the University of Kent, “particularly since it seems that only small changes in bacterial genomes within the microbiome have these effects.”
Indeed, the team has already shown that colanic acid can also extend the life of fruit flies, and can affect the mitochondria of mammalian cells in the same way that it did those of the worms. “I don’t want to speculate too much, but that makes us positive,” Wang says. “We’re now starting experiments with mice.”
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