Senescence and the zombie cells

What happens when cells can no longer divide? They go into programmed cell death, even Apoptosis and make room for new cellsBut that doesn't always seem to be the case. There is an intermediate state that the cells can switch to: the so-called “senescence”. The word comes from Latin and means something like “growing old” or “aging“These senescent cells have accumulated too much damage to their genetic material and can no longer divide – but they do not die either.

What probably protects us from degeneration when we are young can become a burden on the body later on. The more senescent cells accumulate, the greater the “burden of the undead.” In this relatively new field of research, scientists are investigating the effect of so-called senolytics. These are molecules that help the body get rid of unnecessary, senescent cellsWe will give you an overview of this exciting field of aging science, explain what is meant by the Hayflick limit, how senescent cells contribute to the aging process and what options are being researched to drive the "undead" out of our organism.

The Cell Cycle

First of all, we need to look at the cell cycle. Don't worry, it won't cover every single molecular step, but rather it will give you an overview so that you can better understand the effect of senolytic molecules.

Our body consists of hundreds of millions of cells. Whether skin, muscle, intestinal, immune or blood cells – all these different cells fulfil their function in the body, age over time and ultimately lose their function – this is a completely normal processIn order to maintain the higher-level body functions, the cell populations undergo permanent renewal processes, where the cells divide and from stem Cells be replaced.

The Hayflick Limit

Let’s make things a little more practical. A connective tissue cell (fibroblasts) is a rather misshapen cell that you can imagine as a large factory. Inside the cell there is a nucleus (which contains the DNA) and around it various cell organelles (production machines) that produce all kinds of proteins. The most common are the glycosaminoglycans and collagen produced.

If a connective tissue cell wants to multiply, it does so by first making an exact copy of its DNA. This "growing guide" describes exactly which components are needed to assemble a new fibroblast. As soon as everything has been copied, the cell divides and two identical connective tissue cells are created.

However, a little DNA is always lost during this process. The ends of the DNA, also Telomeres called telomeres, become shorter. Fortunately, this is not a problem at first, as nature has come up with two very clever protective mechanisms. Firstly, the telomeres are a type of Protective shield. There is no relevant information for proteins and if some base pairs are lost here, the “blueprint” is still correct. In addition, there is the enzyme Telomerase, which can replenish the used ends. However, since telomerase is only active in selected cells (stem cells, tumor cells), there is a certain upper limit to division.

One of the first to discover this phenomenon was the Professor Leonard HayflickAs early as 1961, he was able to prove experimentally with fibroblasts that this natural limit beyond which cells no longer divide actually exists. Depending on the type of cell, this “Hayflick limit” at about 50 cell divisions.

Did you know?
With a share of about 30% collagen is the most common protein in the bodysystem. (R) It has very different tasks. In bones, collagen is required to be as strong as possible, while blood vessels need to be more elastic and stretchable. This is no problem for the versatile protein collagen. However, with age, the body's collagen production decreases. This leads to skin aging and the formation of wrinkles. With the help of Collagen peptides you can make up for this loss. (R)

Cellular senescence – what happens after the Hayflick limit?

The fibroblast has now reached its personal division limit. After 50 divisions, too much damage has accumulated in the DNA. Accordingly, the “blueprint” for a new cell would contain critical errors that could pose a serious threat in the form of degenerated cellsSo what happens to the fibroblast?

You have probably heard of the Apoptosis belongs to programmed or controlled cell death. The counterpart to this is the necrosis, where cells die due to damaging external influences such as heat, cold, lack of nutrients or oxygen and also trigger an inflammatory reaction in the surrounding tissue.

The safer option is apoptosis. If our fibroblast has reached its Hayflick limit, it enters this state. The individual components are carefully broken down, later transported away by phagocytes and partially recycled.

Our body has a very strong ability to recognize aged or senescent cells. This is the only way they can be efficiently eliminated through programmed cell death. At least, this is the case in a young, functioning organism.

Senescence – Cells in Limbo

In reality, not all cells that have reached their “Hayflick limit” are recognized. To prevent these cells from multiplying uncontrollably, an intermediate state has emerged in evolution: SenescenceWhy cells either undergo apoptosis or enter the intermediate state is still not fully understood.

At a young age, senescence can be a kind of protection against cancer. From our organism's point of view, it is better to keep a cell quiet than to risk degeneration. In terms of quantity, the undead cells only become a problem in old age. In mouse experiments, In young animals only about 1,4% of the connective tissue cells are senescent – ​​in old mice it is ten times as much.

In old age, the body’s own Immune system no longer able to recognize all undead cells in a timely manner and initiate apoptosis. The result: the population of senescent cells is constantly increasing. This is not only due to the age-weakened function of the immune system, but the cells have also developed mechanisms to resist cell deathThis is based on so-called “pro survival networks”. In addition, the senescent cells can “infect” their surrounding cells and “shut them down” even if they were previously healthy.

Did you know?
In the course of evolution, our body has learned many clever ways to sort out defective cells. One of them is Autophagy – also known as “cell-owned garbage collection” If a cell becomes dysfunctional due to the "waste" it produces before it reaches the Hayflick limit, it can be saved from programmed cell death by autophagy. This sophisticated method recycles "waste" within the cell and the cells regain their function.

The field of autophagy is also represented in aging research and one of the most exciting molecules in this context is SpermidinIt can help your body recycle old cells.

SASPs – a dangerous cocktail

What makes senescence or senescent cells so "dangerous" for the body? Sure, they represent a lot of "useless ballast", but that alone does not explain their role in diseases such as diabetes, pulmonary fibrosis, cardiovascular disease, obesity or dementia.

Senescent cells no longer divide, but that does not mean that they are not metabolically activeOn the contrary, these “undead” produce a lot of messenger substances, the total of which is known as “senescence-associated secretory Phenotype", short SAS, This complicated name hides hundreds of different molecules. From inflammatory mediators such as interleukin to protein-splitting protases and growth signals.

The exact role of this “protein cocktail” is currently being researched. At a young age, for example, it can lead to improved wound healing, but as we age, there is increasing evidence that SASPs are responsible for many of the negative consequences of senescent cells. In all probability, as always in nature, there is a balance. Both too little and too much are harmful to us.

What are senolytics?

Now that we have looked in great detail at the basic biology of “undead” cells, the question now arises as to what we should do with this knowledge.

Scientists were able to show in animal experiments that the elimination of senescent cells – in this case in muscle, fat and eye tissue – led to a later onset of age-related diseases. To do this, they used a protein with the complicated name p16^Ink4a and specifically switched it off in the mice. (R)

This is just one of many ways that have been shown that eliminating senescent cells in old age leads to improved health. It is not quite that simple. We now know that there is not "one" marker for senescence, but many different ones. Cells have also developed different strategies to protect themselves against the immune system.

For this reason, several substances are currently being researched that can support the body in eliminating "undead" cells in various ways. These substances are called senolytics.

Did you know?
p16^Ink4a can also be found in the senescent liver cells. If these accumulate over a longer period of time, the inflammatory signals from the cells (SASP) contributes to increased inflammation and increased fat accumulation in the liver. The most common cause is non-alcoholic fatty liver disease, also known as NAFLD, called. (R,R) In this study (R), the researchers were able to show that both the genetic elimination of p16^ink4a, as well as therapy with Quercetin and another substance the number of “undead” cells decreased. As a result, less fat accumulated in the liver, which led to an improvement in the disease. about a quarter of all people have NAFLD (R), this is a promising discovery for the future.

luteolin

Also on this list is the luteolin, another representative of the flavonoidsLuteolin is found in olive oil, rosemary and thyme. It can interfere with the metabolism of senescent cells, for example by NF-kB, an inflammatory mediator, is downregulated.

Sport and fasting – this is how we get rid of senescence

Not only drugs can affect senescent cells. Fasting and exercise also have demonstrable effects on our body. In this Review, a summary of many individual studies, it was also shown that exercise could reduce the number of senescent cells.

Among other things, they demonstrated that the levels of p16^Ink4a were lower in people with higher levels of physical activity. Other markers were also positively influenced in both human and animal studies.

In summary, the field of senescence and senolytics offers a promising approach for future interventions. The discovery of "undead" cells initially caused a lot of confusion, but more and more research is slowly shedding light on this complex topic. Senescent cells are not always bad - especially in small quantities and at a young age, they seem to have an evolutionary purpose. As we age, however, the large number of "undead" cells and the "toxic cocktail" of SAPS cause our body more and more problems. This is where the research field of senolytics promises possible new approaches.

Our preview of Quercetin and luteolin Two natural substances have already been successfully tested in various studies and you can also strengthen your own senolytic powers with a little exercise.