Just take a break – to recover. We humans like to do that. One might even be inclined to say that it is in our nature. If you take a closer look at the basis of our existence, the cells, then this thought is actually quite close to the molecular reality. Even the cells take a break under certain circumstances or stop dividing. This state is referred to as cellular senescence.
Colloquially, these cells are often referred to as "undead" or "zombie cells". And they are quite close to the truth, because senescent cells are neither dead nor truly alive. We will discuss this rather new discovery in science in two articles.In the article about Senolytics we show you the scientific background and give you tips from science on how to get rid of senescent cells. This article is more about senescence and its role as one of the molecular Hallmarks of Aging.
Hayflick limit and telomeres – how do the "undead" arise?
Senescence (from Latin senescere; to age) plays a significant role as the endpoint of some processes in the body. In the previous articles on genomic instability and on mitochondrial dysfunction we have already become acquainted with senescence. In young years, senescence seems to be a kind of safe intermediate state for degenerated cells.
Cellular senescence is fundamentally a stable standstill of the cell cycle. The first discoveries in this direction were made in the early 1960s by scientists Leonard Hayflick and Paul Moorhead. They found that human fibroblasts (connective tissue cells) in culture can divide a maximum of about 50 times before they suddenly stop and age.
What is common today was groundbreaking back then. In those long-gone days, the prevailing view in cell biology was that all cultured cells are immortal. Hayflick overturned this dogma with his experiments and found that only cancer cells have this characteristic.The phenomenon of the division limit is called replicative senescence, or after its discoverer: Hayflick limit. Currently, we know that the senescence observed by Hayflick is caused by telomere shortening. However, there are also other stimuli, apart from telomere wear, that can trigger cellular senescence. If the telomeres are too severely degraded, either the apoptotic process begins or cells become senescent. How is senescence measured? In addition to damage in the area of telomeres, particularly two other points contribute to cellular senescence: non-telomeric DNA damage and the INK4/ARF locus on the DNA.Both occur in connection with chronological aging and are capable of inducing senescence – this has been demonstrated in experiments. But how is such a thing actually proven?
First of all, it is important to note that senescence is not directly measurable. There is no laboratory parameter that provides a specific value after a blood draw. Therefore, researchers use so-called surrogate markers that allow for an indirect conclusion. In the case of cellular senescence, DNA damage or the senescence-associated β-galactosidase (SABG) is used as a marker.
In a study from 2009 , quantification was performed in mice based on these two parameters. The results showed values of about 8% senescent cells in young mice and about17% in very old mice. When looking at the values by organs, similar values were found in skin, lung, and spleen. No changes were observed by the researchers in the heart, kidney, or muscle tissue.
This is exciting because it means that the extent of cellular senescence differs from tissue to tissue. For tumor cells, for example, there is experimental evidence that they are strictly immuno-monitored and can consequently be efficiently removed.
Aging and cellular senescence
We now know that the amount of senescent cells increases with age. This observation has been made in numerous studies. Why is this the case? Without going into too much detail, there is a simple answer to this.Too many of these "undead" cells are produced or too few are broken down. The truth lies somewhere in the middle. It would be too simplistic to say that aging research now has a new enemy image. The connection is not as linear as it seems at first glance. Possibly, the main purpose of senescence is quite different. Namely, the prevention of the proliferation of damaged cells and the triggering of clearance by the immune system. We remember that DNA damage is a surrogate marker used to quantify senescence. Senescence is a beneficial compensatory reaction to free tissue from broken and potentially even tumorous cells.
The prerequisite for this, however, is an effective cell replacement system. Because the senescent cells must first be removed and subsequently replaced in order to maintain homeostasis or balance in the tissue. This is exactly where the catch lies regarding aging.
This replacement system tends to become inefficient with increasing age, which is reflected in a lack of regenerative capacity of cells. This leads to the accumulation of senescent cells, which sooner or later worsen the damage and accelerate aging. However, the mere presence of a steadily increasing number of inactive cells is not decisive for this. Rather, it is the secretome that is the culprit.
The secretome sounds mysterious at first, but it is "only" the totality of all secreted substances of a cell. In the case of senescent cells, the secretome is particularly rich in inflammatory and destructive substances. It is referred to in science as Senescence-Associated Secretory Phenotype (SASP). You can learn why these inflammatory substances can cause problems in our article on Inflammaging.
Cell division as a recycling mechanism is strictly regulated in the body.
Mitogenic signaling - when something goes wrong during cell division
In addition to DNA damage, excessive mitogenic (cell division inducing) signaling is associated with senescence. You can remember mitogen more easily as MITOGEN erating. Mitosis is the process of cell division. There are quite a number of these mitogenic or also oncogenic (cancer-causing) changes. In response to these signals, senescence can be triggered in the cell. There are numerous mechanisms for this as well, but the INK4a / ARF locus is unmatched in significance.
INK4a / ARF locus and p53 – what do the abbreviations hide?
Don't be alarmed, the topic is not nearly as complicated as the headline suggests. The extent of p16INK4a (the protein produced based on the INK4a gene) is related to chronological age in all analyzed tissues, both in mice and humans. This colossal relevance is remarkable. The INK4a/ARF locus (location on the DNA) has been identified in a meta-analysis (highest scientific evidence) as the genomic location associated with the highest number of age-related pathologies .
These include various types of cardiovascular diseases, diabetes, glaucoma, and Alzheimer's disease. p53 is another protein that induces senescence. "p" always stands for protein in the context of nomenclature.
Did you know? The protein p16Ink4a is also detectable in senescent liver cells. An accumulation of these "zombie" cells over time contributes to the activation of pro-inflammatory signals from the cells, also known as the Senescence-Associated Secretory Phenotype (SASP), which can lead to increased inflammation and an elevated accumulation of fat in the liver. This process is often associated with non-alcoholic fatty liver disease (NAFLD).
Japanese cord tree as a potent source of quercetin: Quercesome is 20 times more bioavailable than conventional quercetin powder due to phospholipids.
Opposite, yet the same?
Due to the senescence-inducing function of p16INK4a and p53, researchers proposed the plausible hypothesis that the two proteins contribute to physiological aging. The age-promoting effect can therefore be neglected when considering the much more important benefits in tumor suppression. In fact, the topic is somewhat more complicated, which contradictory research results suggest.
In mice that aged prematurely due to extensive and persistent cell damage the elimination of p16INK4a and p53 resulted in an improvement in overall organism function. In another experiment, mice with a slight increase in both proteins had a longer lifespan. This survival advantage was greater than what a lower incidence of cancer would suggest.
The activation of the two mentioned proteins is therefore a beneficial response regarding the development of tumors and thus cancer. This prevents the spread of mutated cells. However, when damage is widespread and affects a large proportion of the cells in our body, the body can no longer keep up: the regenerative capacity is exhausted.Under these conditions, the activation of INK4a / ARF is detrimental and accelerates aging.
Cellular Senescence – Conclusion
Cellular senescence is a useful compensatory response to damage, but it can also accelerate aging and be detrimental to health if tissues can no longer recover adequately. Ultimately, based on studies, there are two contradictory intervention approaches that can both contribute to longevity so far.
On one hand, a tumor suppressor effect has positive effects on aging. On the other hand, the elimination of senescent cells in experiments shows a delay in age-related diseases. The "undead" are therefore not completely useless.
Presumably, it is like always in nature. In the right balance, senescent cells are beneficial for our health, as they help us z.B. to freeze damaged cells so that they do not degenerate further. On the other hand, the number of senescent cells can increase so much with age, and thus also the inflammations, that age-related diseases are promoted.
In the next article of this series, it will be about the eighth hallmark of aging: stem cell exhaustion.
