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Increasing the health span – with the right microbes

Our microbiome consists of trillions of microorganisms, mostly bacteria and fungi, that live in our intestinal tract and on our skin. In recent years, scientists have discovered that they have a significant influence on our health and well-being. Newest research reveals that they also shape the way we age. Filipe Cabreiro from the CECAD Cluster of Excellence on Aging Research has the details.

Interviewer: Susanne Kutter

Professor Cabreiro, what do the organisms of our microbiome have to do with aging?

A lot. We now know with certainty that a disruption or a positive change in the intestinal microbiome – the so-called gut flora – has direct and causal effects on longevity and health. It is still a fairly young research field, but if we look at publications on the topic, we can see an explosion: In the 2000s, there were hardly any papers on the microbiome. Around 2010, there were about 1500 per year. Now, in 2023, we already have over 130,000 publications – and the year is only halfway through.


How did you come up with the idea of a connection between gut flora and aging?

Actually, that was not my idea at all. It was developed more than 100 years ago by Ilya Ilyich (or Élie) Metchnikoff, who won the Nobel Prize in Physiology or Medicine in 1908 for his work on immunity together with Paul Ehrlich. Metchnikoff firmly believed that the microbiome regulates longevity. That’s why he drank kefir every day – a drink that contains very high levels of lactic acid bacteria, even more than yogurt or sour milk. He coined the term probiotic for these microbes, which we still use today. He wrote a paper called »The Prolongation of Life«. The subtitle was »Optimistic Studies« because he had absolutely no evidence for his thesis. But based on his work on immunity, he assumed that the »good« bacteria that kefir contains displace harmful bacteria, thus preventing inflammation and delaying aging and death.

Nobel Prize winner Ilja Iljitsch Metschnikow already suspected at the beginning of the 20th century that "good" bacteria can displace those that cause disease. This works particularly well with our intestinal flora.

Did it work? Did he reach a very old age?

In fact, Metchnikoff died in 1916 at the age of 71, which is a pretty impressive age considering the circumstances of the time. Of course, that doesn’t prove anything, it’s merely an anecdote. But in principle, he was right. Today we have evidence to prove his assumptions.


What kind of evidence?

The most direct connection we can find is that the life span, and particularly the health span, can be drastically extended if we transfer the microbiome of a younger animal to an older one. Younger microbiomes have more beneficial microbes than older ones, as experiments with various model organisms such as flies, fish and mice have revealed. 


What do you mean by transferring the microbiome?

Actually, that’s kind of disgusting… But it’s a well-established and very helpful procedure in human medicine. It’s called faecal microbiota transplantation and is the therapy of choice for patients suffering from a Costridium difficile infection, which causes serious intestinal inflammation. This bacterium – we call it C. diff. – is a normal component of our microbiome. We all have it in us. But after treatment with antibiotics, it can take over because it has very effective mechanisms to escape the treatment. 
While all other microbes are killed by the antibiotics, this type goes into a kind of hibernation because it can form resistant spores. As soon as the treatment ends, these spores germinate, colonize the intestine and cause an infection that is then very difficult to treat with other antibiotics. But this microbe has a weak spot: It does not thrive well in the company of other microbes. If stool, and with it a large number of other microbes, is transferred to the affected patient by means of colonoscopy, the infection can heal.


Just like that, from one person to another? 

Of course, the donor must be healthy – and the transplant is tested for pathogens and viruses before transfer. But after such treatment, symptoms usually improve very quickly. The success rate in eradicating or controlling C. diff. infection is just over 90 percent, which is really remarkable, isn’t it? Patients completely recover from the infection.
But in general, and far beyond these intestinal diseases, what is interesting for us researchers is that you can in principle control microbes with other microbes. So the transplant of faecal matter has become a very important research topic – not least of all in aging research.
 

How does the microbiome of an older person differ from that of a younger one?

It is clearly different, but we have to realize that we’re talking about a very, very complex ecosystem. We’ve found thousands of different microbes, all producing molecules that haven’t even been properly characterized yet. We don’t yet have the tools to fully understand what they all actually do. 
 

Filipe Cabreiro assembles a team of the best microbes that could age us healthier in the future.

Basically, most of us get our microbiome passed down from our mothers very early in life. It still changes a lot in the first four years, especially when we start eating solid foods. But then it stabilizes and remains very stable until middle age. But as we get older, that stability is lost and our microbiome becomes more diverse again. We don’t know exactly what triggers this change, but a clear hallmark of aging is that our microbiome changes in a negative way. Certain microbes accumulate that are associated more with disease than with health.


Only in humans or also in animals?

Animals are affected as well. Since such typical changes also occur in mice, fish and flies, researchers concluded that many age-related changes must be related to the intestine. Because the intestine also changes with age: the intestinal wall becomes more permeable. In consequence, some molecules from the microbes enter the bloodstream. This, in turn, triggers inflammation, which then leads to even more permeability. It’s a vicious cycle, because the inflammation and increased permeability also lead to further changes in the intestinal environment. As a consequence, “unhealthy” microbes can proliferate in abundance.

Can this process be stopped in any way?

That is exactly what we are exploring: Can we understand the processes and relationships and then reverse what is happening? So far, the only way to do this is to transplant the microbiome from a younger organism. This has been done very successfully in fish, for example. We take the microbiome from a young fish and transplant it into a middle-aged fish. To control the results, we also transplant the microbiome from another middle-aged fish to yet another one. Then we look at how long the animals live and measure cognitive function, physical performance and other parameters to determine health status.


What was the outcome?

The fish that received the microbiome from the young fish actually lived much longer than those that received the control. This shows that the mere presence of various microbes is sufficient to extend lifespan. Also, a »rejuvenated« microbiome tends to be associated with increased longevity and improved health.

Bacteria isolated from human stool could one day alleviate the symptoms of some age-related diseases.

How can humans benefit? 

The problem with humans is that our microbiome changes much more than that of animals because, unlike fish and mice, we are constantly changing our diet. Animals usually have the same diet all the time, and it is much easier to transplant the stool of animals and then study that in a controlled way. Such a therapy might be helpful for progeria syndrome, a rare but severe hereditary disease which leads to premature aging in childhood. But we really do not want to establish faecal transplantation as a method. We are looking for a more elegant and practical solution.


What sort of solution?

Instead of mass transfer by means of stool transplant, some research groups are focusing on a single microbe candidate. However, we believe that this cannot do justice to the tremendous complexity of our community of gut microorganisms. That’s why we are putting together a team of 15 candidates. This kind of microbe cocktail could be tested in various individuals so that we can see – okay, these 15 microbes, if administered to all these people, are proven to be safe and beneficial.


How far is this research?

We are still in the process of identifying the right candidates for our team. CECAD here in Cologne offers ideal conditions for this work because we have mice that are raised completely germ-free. They live in these bubbles in which there are no microbes. That means they also have no intestinal flora at all, except for what we implant in them. That way, we can recognize causalities, we can show the precise impact of this or that microbe on the physiology of the host animal. We can use these germ-free animals to test interventions, and we can also understand how the intervention of a drug that might improve lifespan depends on the presence of these microbes. Last but not least, we can test whether and how the introduction of certain helpful microbes is particularly successful – whether they change lifespan or health status in any other way. In sum, you can do all kinds of manipulations that are very difficult in conventional mice. That’s actually one of the reasons why I chose to come here to Cologne from London. 
 

Kefir: the fermented sour milk product from the Caucasus region contains particularly high levels of lactic acid bacteria and is considered to be beneficial to health.

Wouldn’t it be easier to just drink kefir every day? Or to consume one of the probiotic products that have been available on the market for decades?

You could try it, but it is not a very scientific approach and would probably mostly benefit the companies that make these products. The probiotics industry is a multi-billion-euro industry, but not a single probiotic has been proven to be effective. They are chance finds and the explanatory models may or may not be correct. Moreover, many of the probiotics you buy in stores aren’t even alive anymore. They are really just dead cells. Others don’t stay in your body and multiply, they just get excreted.

So, it would be better to wait for your microbe cocktail?

Yes, definitely. We want to establish a set of microbes of which we actually know exactly what each one does and what it produces. In fact, we will genetically design these microbes to have a kind of emergency stop button. Imagine that these helpful organisms settle in the human intestine, but then have some unforeseen side effects. Then we have to get rid of them somehow. Eradicating them with antibiotics would not be elegant, because then all the other microbes that naturally occur there would also suffer. So we are artificially building in a so-called kill switch: a mechanism that reacts to a substance. It is completely harmless to the rest of the body, but switches on a suicide programme or causes the cell membrane to dissolve – only and exclusively in our designer microbes. 


Does that mean that your life-prolonging cocktail consists of genetically modified organisms (GMOs) that fall under various national and international GMO regulations?

Yes, that is correct.

Do you think you can convince people that that’s a good thing?

It will certainly be an interesting discussion. At the moment, the answer is probably no. Will that change over time? Perhaps. But I firmly believe that if we can one day prove that this therapy really works and allows us to grow old in good health, people will recognize its benefits and accept it.

The Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD) was the first Cluster of Excellence to be established at the University of Cologne in 2007. It investigates the causes that underlie both aging and triggering a broad spectrum of age-associated diseases. The molecular basis of these processes will be understood and new therapies for age-associated diseases such as cardiovascular diseases, chronic kidney diseases, diabetes, cancer and neurodegenerative disorders will be derived from this. Currently, 61 research groups with a total of over 650 researchers from 59 countries are working in close interdisciplinary and international collaboration at CECAD. The location of the CECAD Research Center and the nearby Max Planck Institutes for Biology of Ageing and Metabolism Research on the Life Science Campus in Cologne contribute to pooling various competencies in one location.

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