11 Hallmark of Aging: Dysbiosis

For some years now, the microbiome has increasingly become the focus of public interest. The billions of bacteria that live in our bodies have a previously underestimated influence on whether we are healthy or ill. The exact connections are not yet fully understood, but one thing is certain: we live in a close symbiosis with our bacteria.

The better we understand this interaction, the better we can take advantage of it. If we eat a lot of plant-based fiber, for example, our intestinal bacteria can convert it into short-chain fatty acids, which have a number of health benefits. It is also beneficial to maintain as much diversity as possible in the microbiome.

As we get older, this symbiosis seems to become increasingly dysbiosis. Fewer and fewer of the "good" bacteria live in our gut and the "bad" ones take over. It is not so easy to break this down to one type of bacteria, as each microbiome is highly individual and depends on many factors. For example, ethnic origin, living conditions, food choices, lifestyle, etc.). Changes in the microbiome are associated with some chronic diseases, such as diabetes, cardiovascular disease and cancer. Find out all about the topic here.

More than just bacteria - our microbiome

Entire books could be written about the microbiome. Hardly a day goes by without a new study being published on the subject. And the interest in research is more than justified. The microbiome is dependent on us and vice versa. How exactly this symbiosis works is gradually being uncovered. Roughly speaking, we need the microbiome to get some nutrients from our food. Our body does not have the right enzymes to break down every nutrient. And this is where the microbiome comes into play.

What would normally only be "waste" for us, such as fiber, can be digested by our microbiome. The bacteria are even dependent on being "fed" by us. In return, they produce some substances that are beneficial to our health. These include secondary bile acids, vitamins, amino acid derivatives and short-chain fatty acids.

In addition, the microbiome appears to be closely linked to our intestinal nervous system - a gigantic network of nerve cells that surrounds the entire length of our intestines. Our second brain, if you like, or our "gut feeling". And this enteric nervous system is of course also in communication with our central nervous system.

As you can see, the microbiome is complex and its networks and effects are even more complex. This does not always make it easy to conduct studies. Nevertheless, scientists have been able to find out a lot about ageing. More on this in a moment.

It's all about diversity - symbiosis instead of dysbiosis

Before we look at what happens when the microbiome is not working to our advantage, we need to ask ourselves what a healthy microbiome is in the first place. This question is more difficult to answer than one might think at first glance. There are countless studies on this and the findings can be defined as follows: The microbiome is very individual. Which bacteria did we pick up from our childhood? In which country were we born? Which genes do we carry within us? What was our diet like as a child? Did we have serious intestinal infections? How do we eat? Do we eat a lot of fiber? And so on.

It is widely recognized that we develop our microbiome in early childhood and that it generally remains stable throughout adulthood (unless you radically change your lifestyle or environment).

The older we get, the more the diversity of bacteria in our gut decreases. Researchers see this as one of the main reasons for age-related diseases. An unbalanced microbiome makes us susceptible to an excess of "bad" bacteria.

Clostridium difficile is an impressive example of this. This small bacterium lives in our intestines and initially does not cause much of a stir. However, if we have a more severe infection that requires special antibiotic treatment, this bacterium has a survival advantage. While the majority of bacteria in our intestines die, C. difficile survives and begins to multiply rapidly as there are suddenly no more competitors. The result is a severe intestinal infection that often has to be treated in hospital.

Dysbiosis using the example of p-Cresol

There are hundreds of metabolic processes that all have a potential impact on our health. To simplify things a little, we'll show you an example of a fairly well-researched metabolite: p-cresol

In the ELDERMET study, 500 people, all over 65, were tested for their microbiome and possible metabolic products. This showed that participants with higher stool concentrations of p-cresol exhibited increased frailty.

So what is p-cresol? This molecule is produced by the fermentation of the amino acid tyrosine in our intestines. The sulphated version of the molecule is excreted via our kidneys. As long as our kidneys are healthy, this does not appear to be a problem. However, if the filtration rate decreases and the p-cresol level in our blood rises, it seems to become problematic.

High p-cresol levels are associated with the development of cardiovascular disease and they have a toxic effect on the filtration system in our kidneys. This seems to be a vicious circle. People with poorer kidney function often have a dysbiosis of the microbiome. There is an increased presence of aerobic bacteria, which promote the production of toxic metabolites, including p-cresol. Perhaps this is a possible starting point for the future.

Tryptophan metabolism: from symbiosis to dysbiosis

Another important metabolic process in our gut is the tryptophan pathway. Tryptophan is an amino acid that we absorb through food, for example. Our intestinal bacteria have various ways of metabolizing this amino acid. We show you the three most important ones:

• Kynurenine pathway (Kyn): Tryptophan is broken down to kynurenine via the enzyme IDO (indoleamine-2,3-dioxygenase)
• Serotonin pathway: Our intestinal bacteria can convert tryptophan into the "happiness hormone" serotonin. A full 90% of our serotonin is found in the gut! Tryptophan can also be converted via this axis into melatoninthe sleep hormone
• Indole pathway: The third way of tryptophan degradation is the indole pathway. Higher indole concentrations in older people have been associated with increased fitness. An increase in indole metabolites has also been shown to increase lifespan in mice

Dysbiosis as a hallmark of aging: It all depends on the balance

Some studies on tryptophan metabolism have concluded that an imbalance can contribute to disease. For example, if the above-mentioned enzyme IDO (the IDO-1 subclass to be precise) is over-activated, we find more kynurenine than normal in the body compared to serotonin. This excess kynurenine is associated with a number of diseases. For example, it has been shown that depressed people often have an overactivation of IDO-1, which results in lower serotonin levels. One of the hypotheses is that this contributes to depression.

Note: The long-held scientific hypothesis that low serotonin levels are the trigger for depression is not entirely correct. Serotonin does play a role in the disease, but it is not so easy to break it down.

Chronic inflammation can increase IDO activity and it can therefore be assumed that inflammation also contributes to the dysbiosis of our microbiome via this pathway.

Inflammaging and dysbiosis - two hallmarks with a close link

As we have just seen, chronic inflammation can have a negative effect on our microbiome. But it also seems to work the other way around, at least that's what experiments on mice suggest. Two populations of mice were used for this. One was young and healthy mice and the other older, sick mice. The microbiome of the older mice was then transferred to the younger mice. The result was that the younger mice showed significantly more signs of inflammation, i.e. higher inflammatory markers.

Conclusion

The microbiome is one of the most exciting fields of research and the disruption of the balance seems to contribute to some diseases as we age. We lose the diversity of bacteria that keep us healthy and this is why dysbiosis has been included as one of the Hallmarks of Aging. In the future, we will certainly see some therapeutic approaches that reverse this dysbiosis.

The next article in this series deals with the twelfth hallmark of ageing: altered autophagy.