Longevity, Magazine

Senescence - what "undead" cells have to do with ageing

Senescence Senolytics Article image

What happens when cells can no longer divide? They go into programmed cell death, also known as apoptosis, making room for new cells. But this does not always seem to be the case. There is another intermediate state that cells can enter: so-called "senescence". The word comes from the Latin and means something like "getting old" or "ageing". These senescent cells have accumulated too much damage to their genetic material and can no longer continue to divide - but they do not die either.

What probably protects us from degeneration at a young age can later become a burden on the body. 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 to get rid of superfluous senescent cells. We will give you an overview of this exciting field of ageing science, explain what is meant by the Hayflick limit, how senescent cells contribute to the ageing process and what possibilities are being researched to expel the "undead" from our organism.

The cell cycle

First of all, we need to look at the cell cycle. Don't worry, it won't be about every single molecular step, but rather to 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 fulfill their function in the body, age over time and ultimately lose their function - this is a completely normal process. In order to maintain the body's overarching functions, the cell populations undergo permanent renewal processes, whereby the cells divide and are replaced starting from stem cells.

3D representation of cells in the organism

The Hayflick limit

Let's make the whole thing a little more practical. A connective tissue cell(fibroblast) is a rather bulky cell that you can imagine as a large factory. Inside the cell is a nucleus (which contains the DNA) and around it are various cell organelles (production machines) that make all kinds of proteins. The most commonly produced proteins are glycosaminoglycans and collagen, which are essential for connective tissue.

If a connective tissue cell wants to multiply, it does so by making an exact copy of its DNA as a first step. These "cultivation instructions" describe exactly which components are required 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 known as telomeres , become shorter. Fortunately, this is not a problem at first, as nature has come up with two very clever protective mechanisms. Firstly, telomeres are a kind of protective shield. No relevant information for proteins is stored here and if a few base pairs are lost, the "blueprint" is still correct. There is also the enzyme telomerase, which can replenish the ends that have been used up. However, as telomerase is only active in selected cells (stem cells, tumor cells), there is to a certain extent an upper division limit.

One of the first people to discover this phenomenon was Professor Leonard Hayflick. As early as 1961, he was able to prove experimentally with fibroblasts that this natural limit, beyond which cells stop dividing, actually exists. Depending on the cell type, this "Hayflick limit", named after him, is at around 50 cell divisions.

Did you know? Collagen is the most abundant protein in the body, accounting for around 30%.(R) It has very different functions. In bones, collagen is required to provide maximum strength, while blood vessels need to be elastic and stretchable. This is no problem for the versatile protein collagen. However, the body's collagen production decreases with age. This leads to skin ageing and the formation of wrinkles. With the help of collagen peptides you can compensate for this loss.(R)

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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 become a serious danger in the form of degenerated cells. So what happens to the fibroblast?

You have probably heard of apoptosis programmed or controlled cell death. The counterpart to this is 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 therefore apoptosis. Once our fibroblast has reached its Hayflick limit, it enters this state. The individual components are neatly broken down, later removed by phagocytes and partially recycled.

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

The critical shortening of the telomere ends initiates cellular senescence.
If the telomeres are degraded too much, either the apoptotic process begins or cells become senescent.

Senescence - Cells in Limbo

In reality, not all cells that have reached their "Hayflick limit" are recognized. To prevent them from multiplying uncontrollably, an intermediate state has become established in evolution: senescence. Why cells go into either apoptosis or the intermediate state is still not really clear.

At a young age, senescence can be a kind of protection against cancer. From the point of view of our organism, 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, only around 1.4% of connective tissue cells in young animals were senescent - in old mice it was ten times as much.

In old age, the body's own immune system is no longer able to recognize all undead cells in time and initiate apoptosis. The result: the population of senescent cells increases steadily. However, this is not only due to the age-weakened function of the immune system, but the cells have also developed mechanisms to resist cell death. This is based on so-called "pro-survival networks". In addition, the senescent cells can "infect" their surrounding cells and "shut them down" themselves, even if they were previously healthy.

Did you know? Over the course of evolution, our body has learned many clever ways to sort out faulty cells. One of these is autophagy - also known as "cellular waste disposal". If a cell becomes non-functional due to the accumulated "waste" before the Hayflick limit is reached, it can be saved from programmed cell death by autophagy. This sophisticated method recycles the cell's internal "waste" and the cells regain their function.

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

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According to research, the natural substance spermidine is closely linked to autophagy - a process whose discovery was honored with the Nobel Prize a few years ago.

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.

Although senescent cells no longer divide, this does not mean that they are not metabolically active. On the contrary, these "undead" cells produce a number of messenger substances, the entirety of which is referred to as the "senescence-associated secretory phenotype", or SASP for short. Hundreds of different molecules are hidden behind this complicated name. From inflammatory mediators, such as interleukin, to protein-cleaving protases and growth signals.

The exact role of this "protein cocktail" is still being researched. At a young age, for example, it can lead to improved wound healing, but in old age there is growing evidence that SASPs are responsible for many of the negative consequences of senescent cells. In all likelihood - as always in nature - it is a balance. Both too little and too much are harmful.

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What are senolytics?

Now that we have covered the basic biology of "undead" cells in great detail, the question arises as to what we can do with this knowledge.

In animal experiments, scientists were able to show 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 p16Ink4a and specifically switched it off in the mice.(R)

This is just one of many ways that have shown that the elimination of senescent cells in old age leads to improved health. However, it is not quite that simple. We now know that there is not "one" marker for senescence, but many different ones. The 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 various ways in the elimination of "undead" cells. These substances are called senolytics.

Did you know? p16Ink4a is also found in senescent liver cells. If these accumulate over a longer period of time, the pro-inflammatory signals from the cells(SASP) contribute to an increase in inflammation and an increased accumulation of fat in the liver. The most common cause behind this is non-alcoholic fatty liver disease, also known as NAFLD.(R,R) In this study(R), the researchers were able to show that both the genetic elimination of p16Ink4a and therapy with quercetin and another substance reduced the number of "undead" cells. As a result, less fat accumulated in the liver, which led to an improvement in the disease. Since around a quarter of all people worldwide have NAFLD(R), this is a promising discovery for the future.

Luteolin

Also on this list is the luteolinanother representative of the flavonoids. Luteolin is found in olive oil, rosemary and thyme. It can intervene in the metabolism of senescent cells, for example by down-regulating NF-kB, an inflammatory mediator. The innovative NAD Regenerating Complex (regeNAD) contains this interesting substance along with several other molecules.

Sport and fasting - how to get rid of senescence

It is not only medication that can have an effect on senescent cells. Fasting and exercise also have demonstrable effects on our bodies. You can find a very detailed article on fasting in our magazine.

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 showed that the levels of p16Ink4a 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 equally bad - especially in small quantities and at a young age, they seem to have an evolutionary purpose. In old age, however, the large number of "undead" cells and the "toxic cocktail" of SAPS cause our bodies more and more problems. This is where the research field of senolytics promises possible new approaches.

With quercetin and luteolin, two natural substances have already been successfully tested in various studies and you can also boost your own senolytic powers with a little exercise.

Literature:

  • van Deursen, Jan M. "The role of senescent cells in ageing." Nature vol. 509,7501 (2014): 439-46. doi:10.1038/nature13193 Link
  • Baker, Darren J et al. "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders." Nature vol. 479,7372 232-6. 2 Nov. 2011, doi:10.1038/nature10600 Link
  • Freund, Adam et al. "Inflammatory networks during cellular senescence: causes and consequences." Trends in molecular medicine vol. 16.5 (2010): 238-46. doi:10.1016/j.molmed.2010.03.003 Link
  • Ellison-Hughes, Georgina M. "First evidence that senolytics are effective at decreasing senescent cells in humans." EBioMedicine vol. 56 (2020): 102473. doi:10.1016/j.ebiom.2019.09.053 Link
  • Camell, Christina D et al. "Senolytics reduce coronavirus-related mortality in old mice." Science (New York, N.Y.) vol. 373,6552 (2021): eabe4832. doi:10.1126/science.abe4832 Link

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