Yehrin Tong
As human beings, we are all keepers of a vast menagerie. Every surface of our bodies, inside and out, is teeming with microorganisms. We have microbiomes on our skin, in our mouths and other orifices and – especially – in our intestines.
In recent years, we have grown accustomed to thinking of these internal residents as benign, even essential to our health. Our guts are said to be full of “friendly” bacteria and other microorganisms that do us favours in return for us giving them a cosy home. That is true to some extent, but new research on the role of the gut microbiome in ageing is pointing to what would constitute a profound rethink of this relationship.
In this emerging view, our gut microbes aren’t our friends, but an enemy at the gates. Far from being mutually beneficial, our relationship with them is more like a war of attrition – a war we eventually lose. However, there are ways to postpone the inevitable.
The gut microbiome is a community of perhaps 100 trillion microorganisms – bacteria, archaea, fungi and viruses – that dwell inside our intestinal tract, most abundantly in the colon. It is established early and stays with us throughout our lives, though it is in constant flux. “It’s a very complex, very dynamic community that depends on what we eat, who we interact with,” says at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, Germany.
The ageing microbiome
It also changes as we age. For most of our lives, the composition of our gut microbiome stays within fairly narrow guard rails, and this arrangement works quite well for both parties. We give the microbes food, mostly in the form of dietary fibre. In return, they break down fibrous molecules that we can’t digest and make the energy available to us, as well as supplying nutrients that we find hard to synthesise ourselves. They also work tirelessly to exclude less-friendly microorganisms that would otherwise colonise the gut and make us sick.
As we age, however, the relationship becomes fractious. The species composition of the microbiome changes: strains that were rare or absent begin to dominate while others dwindle or disappear. Overall, there is a loss of species diversity, and with it a narrowing of functional repertoire. This “dysbiosis” is recognised as a . Until recently, however, the causes and consequences of the changes that occur weren’t well understood. Now, it is being seen not just as a hallmark of ageing, but as a direct driver of it.
The idea that the gut microbiome may somehow promote ageing has a long pedigree. In 1907, immunologist Élie Metchnikoff at the Pasteur Institute in Paris, who would go on to win a Nobel prize the following year, published a book called , in which he proposed that our lives many be shortened by “chronic poisoning from an abundant intestinal flora”.
It was speculation, but prescient. “We actually now have a lot of evidence from many studies in many different organisms that the gut microbiome, the microbes themselves, seem to have a key role in regulating ageing,” said from the University of Cologne in Germany at the Aging and Microbiome conference in Jena in October.
, also at FLI, told the conference that for most of our adult lives, our intestinal microbiome is dominated by core species, gut specialists adapted to live inside humans. Though their exact proportions vary from person to person and over time, these species : Ruminococcaceae, Lachnospiraceae and Bacteroidaceae. On the fringes, however, are subdominant species that are highly individualised and mostly acquired from the environment throughout life.
Microbial takeover
After about the age of 50, the core microbiome begins to decline and the subdominant microbiome increasingly runs the show.
The consequences of this takeover are extremely disruptive, according to at University Hospital Schleswig-Holstein in Kiel, Germany. She told the conference that, based on recent experiments in mice, the members of the gut microbiome can be classified into three functional categories: neutral, beneficial and competitive. The first two work in harmony with each other and their host, but the third type are selfishly out for themselves.
In young adulthood, the neutrals and beneficials outnumber the bad guys, but are already on a downward trajectory, with the baddies becoming increasingly prevalent. By the time the mouse is about 30 months old – – competitive species are in the majority. “The neutral or more beneficial ones are going down with age,” said Best. This means that, overall, the microbes don’t work together so well.
Leaky gut and inflammaging
One of the most damaging effects of this shift is a loss of what is known as barrier function, according to at Frankfurt University Hospital in Germany. In a young and healthy gut, the microbes are strictly confined within the lumen – the inside of the intestine – by the gut wall and its thick coating of mucus. But as dysbiosis progresses, competitive microorganisms increasingly breach the barrier, squeezing into the spaces between our cells and eventually entering the bloodstream. This prompts the immune system into action, resulting in low-level inflammation spreading throughout the body. This “inflammaging” is another hallmark of ageing.
“We know that microbial composition and function changes significantly with ageing,” at the Quadram Institute in Norwich, UK, told the ageing research conference. “Concomitant with this, we also see the development of inflammaging, this chronic, low-level, systemic inflammation which contributes to the decline of tissues and organs around the body.” This has led to the question of whether dysbiosis is a cause, consequence or simple correlate of inflammaging, she said.
A high fibre diet helps protect the intestinal lining from being breached by gut microbes StockFood/Gontar, Yuliya
According to at Ulm University in Germany, this is a classic chicken-and-egg question. “Upon ageing, we do know that both systems undergo profound changes,” she told the other researchers at the conference – but which comes first? “Much work has been focusing on what dysbiosis does to immune system function,” she said. “Less is really known [about] what intrinsic ageing of the immune system does to the microbiome.”
To find out, she and her colleagues took haematopoietic stem cells – which give rise to most major immune cells and which, as they age, cause immune function to decline – from young and old mice and swapped them over. The mice had been irradiated to destroy their immune systems, but the transplanted stem cells grew to fill the vacancy. Once the transplanted immune systems had matured, Stahl and her colleagues analysed the recipients’ gut microbiomes via faecal and intestinal cell samples. She found that young mice given an old immune system developed a microbiome typical of older mice, and vice versa. This suggests that ageing of the immune system, or immunosenescence, precedes changes in gut microbial composition, said Stahl.
The implication is that the immune system keeps a lid on the microbiome, but when that lid is lifted, the microbiome is ready and willing to storm the citadel. “This is a big question, but I think there’s something inherent that breaks down first at the host level,” says Cabreiro. “You remove this control over the microbiome and therefore you start having this dysbiotic microenvironment, which then fuels the entire cycle.”
Further evidence that the microbiome turns against us as we age comes from a recent set of experiments in Cabreiro’s lab involving an animal model called the progeroid mouse. This is a strain of laboratory mouse with a mutation in a gene called POLG, which codes for a protein involved in the repair of mitochondrial DNA, the genome of the energy-producing structures within cells. The mutation results in extensive mitochondrial dysfunction, which causes mice to age rapidly in a similar way to children with the premature-ageing syndrome progeria (although this condition is caused by a different mutation).
Signs of ageing
“This mouse shows very clear signs of ageing,” Cabreiro said at the conference, replicating the normal ageing process and living a shorter life. Lab mice naturally live for up to 36 months or more but the progeroid mice are mostly dead within five. During their short lives, the mutant mice rapidly lose weight, muscle mass and fur, classic signs of ageing in a mouse. They also develop immunosenescence and profound inflammation in the colon.
To investigate the role of the microbiome in this process, Cabreiro’s team generated microbe-free mutant mice that completely lack a microbiome. Despite the mutation still being present, these mice lived significantly longer than “colonised” mutant mice and also showed much fewer signs of premature ageing, including in their guts. They still died young, but their maximum lifespan was extended by 26 per cent.
No great surprise there, says Cabreiro. It has been known since the 1970s that microbe-free mice live longer and healthier lives than mice with a flourishing microbiome – although they do show . They are also more resistant to age-related diseases, including cancer and type 2 diabetes.
Costly gut maintainance
This was largely explained by the fact that microbe-free mice don’t encounter pathogens. But that can’t be the whole story, says Cabreiro, because lab mice with a normal microbiome that are sheltered from pathogens are also shorter-lived and less healthy than their microbe-free counterparts. There must be something about having a microbiome that reduces health and longevity.
Discovering exactly what is still very much a work in progress, but there are hints. Cabreiro has found that the energy required to maintain a microbiome exerts a great toll on the host’s metabolism, which could contribute to immunosenescence and general ageing.
Gut microbes seem to play a key role in regulating ageing
This led him to what he calls a provocative idea: maintaining the microbiome is actually a huge burden that ultimately reduces our lifespans and, in an ideal world, we wouldn’t need one at all. “I’m not entirely sure anymore whether there’s any good microbe,” he told the ageing research conference. “We constantly talk about good and bad microbes. From a purely ageing perspective, so far all the evidence that I’ve seen is that germ-free animals are actually healthier and better than any colonised animal. Yes, of course, in the real world, we do need a microbiome, but it does carry a cost.”
But what about all the vital services that our friendly bacteria provide? Again, the fact that microbe-free mice thrive suggests that these microbes aren’t vital at all. Yes, a healthy microbiome provides metabolic services and has important functions, but these aren’t a matter of life or death it seems.
In reality, of course, living without a microbiome isn’t an option. We are surrounded by microorganisms that inevitably colonise us, many of which are dangerous. “If we were living in a condition where we’re not challenged every day, we didn’t have viruses and pathogens trying to kill us, then we would be much better off not having this association,” says Cabreiro. “It’s almost a marriage of convenience.”
Spending time with younger people can rejuvenate an ageing gut microbiome Richard Kalvar/Magnum Photos
This is all in keeping with recent research on how hard our immune systems have to work to – a process called host control. “There are two components to it,” says at the University of Oxford. “Innate immunity, which includes the mucosal barrier to contain microbes and prevent them from being where they’re not supposed to be, [and] there’s also adaptive immunity.” The latter takes the form of antibodies secreted into the gut to eliminate microbes that threaten to worsen those strained marital relations.
“The innate system is probably the part that requires the most resources, or has the most cost for the host,” says Wilde. “I’m not sure how much mucus is secreted in total, but it must be an awful lot, at significant cost.”
He, too, has come to the conclusion that the gut microbiome has been given too much of an easy ride. “There’s this thought that our microbes have our best intentions at heart and they’re inherently good. But I think that heavily misses the mark,” says Wilde. To see their true intentions, consider what happens when control by the host is permanently lifted, he says. “When we die, our microbes eat us. Within 30 minutes or something, you’ve got microbes in your bloodstream and then they go to most of your organs and you swell from inside as they start to break down your tissues.”
Is there any way of postponing that gruesome outcome by exerting host control for longer? “We know that exercise has a really beneficial effect on your immune system,” says Parker, “and because of the interaction between your immune system and your microbiota, that’s the best thing you can do to keep everything working well.”
Microbiome-boosting lifestyle factors
Many other lifestyle factors worsen dysbiosis, says Vehreschild. A course of oral antibiotics can radically and persistently alter the composition of the gut microbiome. The culling of certain classes of bacteria breaks what is known as colonisation resistance – the collective efforts of the microbiome to exclude outsiders – allowing undesirable species to gain a foothold.
Many other therapeutic drugs also weaken colonisation resistance, including anti-inflammatories, antidepressants, diabetes drugs and proton pump inhibitors for controlling stomach acid. A found that 1 in 300 non-antibiotic drugs have this effect.
Poor diets are another source of trouble. Many gut bacteria derive energy from dietary fibre, but will switch to consuming the mucus lining the intestine if they are being starved. Low-fibre diets can also tilt the balance away from these bacteria and towards mucus-eating specialists. This gradually breaks down the mucus lining and leaves the gut wall vulnerable to breaches. “When you take all these little things together, you have a lot of components that look similar to what happens when you look at immunosenescence,” says Vehreschild.
You can also reinvigorate your microbiome by spending time with younger people, because we pick up a lot of our microbes from those around us, says Valenzano.
Faecal microbial transplants
In the longer term, faecal microbial transplants – where young microbiomes are transferred to older people – look encouraging, at least in animal models, says Vehreschild. She is currently trying to set up a clinical trial to test whether these transplants reduce biomarkers of ageing in older people. This is a promising approach, says Parker. “We find consistently that if you transfer young faecal microbiomes into an older recipient, then you reduce some of these markers like inflammation and other indicators of ageing.”
Ultimately, though, if you live long enough, your gut microbiome will eat you alive. Thankfully, that doesn’t negate the things that many of us already do to cultivate a healthy one. But we need to stop thinking of our gut bugs as our friends and start seeing them for what they really are: frenemies. “I think it’s important for the field to move beyond saying that the microbiome is the solution for everything,” says Cabreiro. “It’s conceptually simplistic, and very likely wrong.”
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