Simply take a break - relax. That's what we humans like to do. You might even be inclined to say that it's in our nature. If you take a closer look at the basis of our existence, the cells, then this idea is actually quite close to molecular reality. Cells also 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 this is pretty close to the truth, because senescent cells are neither dead nor really alive. We deal with this rather new scientific discovery in two articles. In the article about senolytics we show you the scientific background and give you scientific tips on how to get rid of senescent cells. This article is more about senescence and its role as one of the molecular hallmarks of ageing.
Hayflick limit and telomeres - how do the "undead" develop
Senescence (from Latin senescere; to age) plays an important role as the final stage of some processes in the body. In the previous articles on genomic instability and mitochondrial dysfunction we have already learned about senescence. At a young age, senescence appears to be a kind of safe intermediate state for degenerated cells.
Cellular senescence is basically 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 discovered that human fibroblasts (cells of the connective tissue) in a culture divide a maximum of around 50 timesbefore they suddenly stand still and age.
What is commonplace today was groundbreaking back then. In those bygone days, the prevailing view in cell biology was that all cultured cells were immortal. Hayflick overturned this dogma with his experiments and discovered that only cancer cells had 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 attrition, that can trigger cellular senescence.
How to measure senescence
In addition to telomere damage, two other points in particularcontribute to cellular senescence: non-telomeric DNA damage and the INK4/ARF locus on DNA. Both occur in connection with chronological ageing and are able to induce senescence - this has been proven in experiments. But how do you actually prove something like this
First of all, it is important to know that senescence cannot be measured directly. There is no laboratory parameter that spits out a specific value after a blood sample therefore, researchers use so-called surrogate markersthat allow indirect conclusions to be drawn. 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, these two parameters were quantified in mice. This resulted in values of around 8% senescent cells in young mice and around 17% in very old mice. Looking at the values by organ, similar values were found in the skin, lungs and spleen. The researchers did not observe any changes in the heart, kidney or muscle tissue.
This is exciting because it means that the extent of cellular senescence differs from tissue to tissue. In the case of tumor cells, for example, there is experimental evidence that they are strictly immune-monitored and can be efficiently removed as a result.
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 great detail, there is a simple answer. There are too many of these "undead" cells being generated or there are too few being degraded. The truth lies somewhere in the middle. However, it would be too short-sighted to assume that ageing research now has a new enemy. The connection is not as linear as it seems at first glance.
It is possible that the main purpose of senescence is quite different. Namely, preventing the proliferation of damaged cells and triggering clearance by the immune system. Recall that DNA damage is a surrogate marker used to quantify senescence. Senescence is u.A. a beneficial compensatory responseto rid tissues of broken and possibly even tumorous cells.
The prerequisite for this, however, is an effective cell replacement system. This is because the senescent cells must first be removed and then replaced in order to maintain homeostasis or balance in the tissue. This is precisely where the catch is with regard to ageing.
This turnover system has a tendency 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 exacerbate the damage and increase ageing. However, the presence of a steadily increasing number of senescent cells alone is not the decisive factor. Rather, the secretome is the culprit.
Secretome sounds mysterious at first, but is "only" the totality of all substances secreted by a cell. In the case of senescent cells, the secretome is particularly rich in pro-inflammatory and destructive substances. In science, this is known as the senescence-associated secretory phenotype (SASP). You can find out exactly 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. Mitogen can be more easily remembered as MITOse GENgenerating. Mitosis is the process of cell division. There are a lot of these mitogenic or oncogenic (cancer-causing) changes. In response to these signals, senescence can be triggered in the cell. There are also a number of mechanisms for this, but the INK4a/ARF locus is unsurpassed in terms of importance.
INK4a/ARF locus and p53 - what's behind the abbreviations
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 tissues analyzed, both in mice and humans. This colossal relevance is remarkable. The INK4a/ARF locus (location on the DNA) was identified in a meta-analysis (highest scientific evidence) as the genomic locus associated with the highest number of age-associated pathologies.
These include various types of cardiovascular disease, diabetes, glaucoma and Alzheimer's disease. p53 is another protein that induces senescence. "p" always stands for protein in the context of the nomenclature.
Did you know The protein p16Ink4a is also detectable in senescent liver cells. 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 increased accumulation of fat in the liver. This process is often associated with non-alcoholic fatty liver disease (NAFLD).
Japanese string tree as a potent source of quercetin: Quercesome is 20 times more bioavailable than conventional quercetin powder due to phospholipids.
In contrast, but still the same?
Based on the senescence-inducing function of p16INK4a and p53, researchers hypothesized that the two proteins contribute to physiological aging. The age-promoting effect is therefore negligible when considering the much more important benefits in tumor suppression. However, the issue is actually somewhat more complicated, as contradictory research results suggest.
In prematurely aged mice due to extensive and persistent cell damage, elimination of p16INK4a and p53 improved the overall function of the organism. In another experiment, mice with a slight increase in both proteins showed a longer lifespan. This survival advantage was greater than a lower cancer incidence would suggest.
The activation of the two proteins mentioned is therefore a beneficial response with regard to the development of tumors and thus cancer. This prevents the spread of mutated cells. But when damage is widespread and affects a large proportion of our body's cells, the body can no longer keep up: its regenerative capacity is exhausted. Under these conditions, the activation of INK4a/ARF is detrimental and aging is accelerated.
Cellular senescence - Conclusion
Cellular senescence is a beneficial compensatory response to damage, but it can also accelerate ageing and be detrimental to health if tissues can no longer recover sufficiently. Ultimately, based on studies, there are two contrasting intervention approaches, both of which can contribute to longevity to date.
On the 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.
It's probably the same as always in nature. In the right balance, senescent cells are beneficial for our health, as they help us z.B. to freeze broken cells so that they do not degenerate any further. On the other hand, the number of senescent cells can increase so much with age and thus also the inflammationthat typical age-related diseases are promoted.
The next article in this series is about the eighth hallmark of aging: stem cell depletion.
