3. Hallmark of Aging: Epigenetic changes

What is autophagy?

Autophagy describes the cell's own recyclingIt is quite normal that proteins or other cell components eventually lose their function or are no longer needed. After all, our requirements change over time. Our cell power plants – the mitochondria – do not last a whole human life. The task of autophagy is to ensure that these remnants are broken down correctly and the components are then reused.

The faulty degradation of, for example, proteins – the loss of proteostasis – we have already Hallmark of Aging can be identified. Incorrectly folded proteins can no longer be unfolded. This carries the risk of clumping. However, since the disposal of proteins is only a small part of cellular waste disposal, the hallmarks of aging have been expanded. Altered autophagy has been a separate hallmark since the last update. We'll show you exactly what happens to it as we age here.

From scissors to acid traps – how is the waste in our cells disposed of?

Before we look at what goes wrong as we age, we should first take a closer look at our recycling system. It is elegantly designed and does its job day after day without us noticing.

Roughly speaking, there are two major systems in the waste disposal of the cellsThe first has the cumbersome name Ubiquitin-proteasome system (UPS) and has two main tasks. On the one hand, the marking (ubiquitination) of misfolded proteins and on the other hand, the proteasomes ensure that these misfolded proteins are broken down into their individual amino acids.

You can see the Proteasomes can be thought of as a kind of filter with highly specialized scissors inside. All proteins that enter the proteasomes are carefully separated and are then available to the cell as new building blocks.

The second major system bears the no less complicated name Autophagic-lysosomal system. This is more complex than the UPS, as it not only splits individual proteins, but in case of doubt entire cell organelles are broken down into their building blocks and these are then returned to the cellular metabolism.

The 4th Hallmark of Aging is largely due to a malfunction of the ubiquitin-proteasome system. This is now about autophagy.

Just as mountains of garbage often accumulate in nature, the same thing happens to us humans as we age.

The Autophagic-Lysosomal System

In our cells, it is not only faulty proteins that are a problem, but also cell organelles that no longer function. The role of ATP and the mitochondria We have already written detailed articles, but they reveal little about what happens when old mitochondria have to be broken down. This happens through the macroautophagy.

Here again, simplified: A shell forms around the old mitochondrion, which can be seen in its entirety autophagosome Now we have a protected environment. This is necessary so that the degradation inside the cell does not destroy the entire cell.

In the next step The autophagosome connects with the lysosome. This is a Kind of small stomach – it contains lots of digestive enzymes, that we need to break down complex molecules. Within this protected environment, everything is now broken down and, as always in biology, there is now a new name. The autolysosome is the connection between the autophagosome and the lysosome.

After digestion, everything that can be reused is returned to the cell and the waste products are transported away with the lymph fluid.

Lipofuscin – when you can literally see your age

In old age our highly specialized recycling system can no longer keep up. If we stay with the lysosomes, this is impressive to see. In addition to their role as "garbage shredder“, these cell organs can also absorb large proteins that no longer have a function in the cell, but are too large to be transported away via the lymph or bloodstream. This “hazardous waste“ is stored in the cell in small capsules called “granules”.

If you look at old nerve or muscle cells under the microscope, you can also see many of these dark spots. A large part of this is lipofuscin. It consists mainly of damaged mitochondria that can no longer be broken down properly. The cellular waste basically "clogs" the cell and thus limits its function. This is probably one of the reasons why mitochondrial dysfunction comes with age.

Age spots can be seen under the microscope not only on nerve cells, but also on aging skin.

More than just bacteria – our microbiome

About the microbiome Entire books can be filled with this topic. Hardly a day goes by without a new study being published on the subject. And the research interest is more than justified. The microbiome depends on us and vice versa. How exactly this symbiosis works is gradually being revealed. Roughly speaking, we need the microbiome to get some nutrients from foodOur body does not have the right enzymes to break down every nutrient. And this is where the microbiome comes into play.

What would normally be considered “waste” for us, such as fiber, can be digested by our microbiome. The bacteria even depend on us to “feed” them. 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 surround our intestines along their entire length. If you like, our second brain 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 connections 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 aging. More on that in a moment.

Diversity is what matters – symbiosis instead of dysbiosis

Before we look at what happens when the microbiome does not work to our advantage, we have to ask ourselves what a healthy microbiome isThis question is more difficult to answer than one might think at first glance. There are countless studies on the subject and the findings can be defined as follows: The microbiome is very individual. What bacteria did we carry with us from early childhood? In which country were we born? What genes do we carry? What did our diet look like in childhood? Did we have serious intestinal infections? What 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 usually remains stable throughout our adulthood remains (unless you radically change your lifestyle or environment).

The older we get, the more the diversity of bacteria in our intestines decreases. The researchers see this as one of the main reasons for age-related diseases. A one-sided microbiome makes us susceptible to an excess of “bad” bacteria.

This can be seen impressively in the example of Clostridium difficile This small bacterium lives in our intestines and initially does not cause much of a stir. If we have a more serious infection, requires special antibiotic treatment,  However, this bacterium has a survival advantageWhile most of the bacteria in our intestines die, C.difficile survives and begins to multiply rapidly because there are suddenly no more competitors. The result is a severe intestinal infection that often requires hospital treatment.

Dysbiosis can be triggered by an overpopulation of the bacterium Clostridium difficile. This is often caused by antibiotic therapy.

Dysbiosis using p-Cresol as an example

There are hundreds of metabolic processes, all of which 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 metabolites. It was found that participants with higher stool concentrations of p-cresol had increased frailty.

So what is p-cresol? This molecule is formed by the Fermentation of the amino acid tyrosine in our intestines. The sulfated version of the molecule is excreted through our kidneys. As long as our kidneys are healthy, this does not seem to be a problem. However, when the filtration rate decreases and the p-cresol level in our blood increases, it seems to become problematic.

High p-cresol levels are associated with the development of cardiovascular diseases and they have a toxic effect on the filter system in our kidneys. This seems to be a vicious circle.People with poor kidney function often have dysbiosis of the microbiomeThere is an increase in aerobic bacteria that 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 intestine 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 will show you the three most important ones:

• kynurenine pathway (Kyn): About the enzyme I DO (indoleamine-2,3-dioxygenase) tryptophan is broken down to kynurenine
• serotonin pathway: Our intestinal bacteria can convert tryptophan into the “happiness hormone” serotonin. A full 90% of our serotonin is found in the intestines! Via this axis, tryptophan can also be melatonin, the sleep hormone
• indole pathway: The third way of tryptophan degradation is the indole pathway. Higher indole concentrations in older people could be increased fitness In mice, too, lifespan was increased by increasing indole metabolites