Zombie cells
Introduction
A major driver of the body’s ageing process is cellular senescence. The term senescence comes from the Latin word senex (= old) and means “to grow old or to be old”. While senescence describes the ageing of the entire organism, cellular senescence refers to the ageing of the cells in an organism. In the 1960s, Hayflick & Moorhead were the first to show in a culture of human fibroblasts in a petri dish that the cells stopped dividing and became senescent after a certain number of cell divisions. Since then, countless research groups have studied the so-called zombie cells to find out how they influence the ageing process and how their destructive effect can be stopped. In cosmetics, zombie cells in the skin have been the target of various active ingredients for some time, essentially trying to keep the cell damage that leads to senescence in check. Now a new mechanism for eliminating senescent cells appears promising. Senolytics could be used in medicine and cosmetics to combat the ageing process
How do zombie cells develop? What role do they play in the skin? How can they be effectively and specifically influenced to rejuvenate skin functions?
Why do vital, intact cells become zombie cells?
Too many cell divisions lead to cellular senescence. This is due to the shortening of telomeres, the repetitive DNA sequence at the end of each chromosome. The job of telomeres is to protect DNA during replication; when they have reached a critical shortening, the cell stops dividing to prevent damage to the DNA and senescence. However, there are other triggers for senescence: too much oxidative stress caused by e.g., UV light exposure, environmental pollutants, causing damage to the DNA. When the DNA is damaged to such an extent that it can no longer be repaired, the damaged cells have to make a decision. Do they continue to divide despite the accumulated damage, passing the damage on to daughter cells and potentiating the damaging effect. If they choose apoptosis, programmed cell death, they prevent the damage from spreading. A third option is senescence, which permanently stops further divisions of the cell.
Senescent cells are also called zombie cells for the following reasons:
Even if they stop dividing, they are not dead. Instead, they block the intracellular mechanism of apoptosis and thus prevent their elimination. In addition, they continue to release signalling molecules, such as cytokines, that promote inflammatory processes. This complex secretory programme has been shown to extend senescence into previously normal neighbouring cells.
Why are zombie cells harmful?
Zombie cells are involved in several important processes, such as embryogenesis and tissue regeneration. They also prevent cells with severe damage from proliferating. The senescent cells that are produced during these processes exist only for a limited time and are usually quickly cleared away by the immune system. If many senescent cells are produced simultaneously over a longer period of time due to oxidative stress, they cannot be cleared away by the immune system and accumulate in the tissue. Characteristic of these zombie cells is a senescence-associated secretory phenotype (SASP) that includes chemokines, inflammatory cytokines (such as IL-1 and IL-8) and matrix remodelling proteases (such as MMP-1 and MMP-2). The SASP thus leads to latent tissue inflammation and changes that accelerate and intensify the ageing process. The stress that the SASP exerts on the surrounding tissue can also turn healthy cells into zombie cells, setting in motion a vicious cycle of ageing. More and more cells become senescent, inflammation increases due to higher SASP uptake, further destroying the extracellular matrix and increasing tissue degeneration and ageing.
Among the best studied cell types affected by senescence are the fibroblasts in the dermis. Fibroblasts are affected by both intrinsic ageing and external aggressive influences, such as UV radiation and toxic particulate matter that can enter the skin. While most keratinocytes in the epidermis can avoid the accumulation of damage through the continued shedding of terminally differentiated keratinocytes, fibroblasts are long-lived and therefore more susceptible to accumulating damage. The SASP of senescent fibroblasts in the dermis leads to persistent inflammatory reactions causing skin redness and dilated blood vessels.
In addition, the breakdown of the extracellular matrix is accelerated, which is why the skin loses elasticity and firmness. That is why it is important to keep the population of senescent cells under control.
How can zombie cells be combated?
There are several options for dealing with senescent cells.
First, prevention: If the damage that can lead to senescence is repaired, the cells will not become senescent. However, this is not possible for all damage that occurs in the cells. The body, and especially the skin, is continually exposed to internal and external stressors.
Another option would be to prevent senescence from occurring despite damage. This would prove detrimental to the tissue, as cells with considerable DNA damage would divide and pass the defects on to the daughter cells. This should be avoided at all costs, because it could lead to uncontrolled cell growth.
The third option has been a promising approach in anti-ageing therapy for several years. Here, senescent cells are eliminated in such a targeted way that the surrounding vital, intact cells are not affected. This new, so-called “senolytic” concept, rids the tissue of zombie cells to reduce inflammation and rejuvenate the tissue.
The term senolytics was first used in 2015 by scientists at the Mayo Clinic and Scripps Research Institute in the US to describe the mechanism by which senescent cells are selectively eliminated without negatively affecting healthy, properly dividing cells.
The targeted zombie cells are induced to undergo apoptosis and then removed from the tissue. By removing the zombie cells, the negative effects and diseases of ageing are reduced and life span is extended. Although this topic of life sciences is still brand new, there are already over 300 scientific publications dealing with the senolytic activity of various substances. So far, the senolytic concept has not been used in cosmetics, despite the great potential it holds for keeping the skin young.
One example is an extract from the leaves of the organic Rhododendron ferrugineum, also called alpine rose, and its senolytic effect on human fibroblasts. A randomised clinical trial with a placebo control group showed a reduction in skin redness and an increase in elasticity.
Clinical anti-ageing study
In a double-blind clinical trial with a placebo control group, 44 women with Northern European skin type aged 40-65 years (mean: 55 years) with redness on the skin of the cheeks were divided into two groups. One group used a cream with 2% Alpine Rose extract, the other a placebo cream. The respective cream was applied by both groups on the entire face and neck twice a day for 28 days. Skin tone was measured with a Spectrocolorimeter CM700-d (Konica Minolta, Japan) and skin elasticity was determined with a Cutometer MPA 580 (Courage + Khazaka, Germany).
In addition, macrophotographs were taken before and after treatment using the Visia Skin Analysis System (Canfield Scientific, Germany).
Results and discussion
Alpine rose extract has senolytic activity.
A challenge in testing for senolytic effects is to distinguish between the effects of senescence-delaying agents, such as antioxidants, which reduce the damage that can lead to senescence, and the actual senolytic activity. To assess the latter, senescence was first induced in fibroblasts with a 2-hour treatment with H2 O2 before the cells were cultured for three more days. Only then, when the senescent phenotype was established, treatment with the potentially senolytic agent was carried out. The number of senescent cells was quantified and compared to the total number of cells. Only agents that eliminate senescent cells without negatively affecting healthy fibroblasts are considered to have senolytic properties.
Treatment with 1% Alpine rose extract significantly reduced the number of senescent cells without affecting the number of healthy fibroblasts. Compared to the control cells, which had 28.1% senescent cells relative to the total cell number, treatment with alpine rose extract reduced the number of zombie cells to 10.1% relative to the total cell number. The effect was similar to treatment with the senolytic Navitoclax, which reduced the percentage of senescent cells to 12.3%. Thus, the Alpine rose extract exhibits senolytic activity.
The increase in skin elasticity and the decrease in redness
In a double-blind clinical trial with placebo control, twice-daily application of 2% Alpine Rose extract over a 14-day period resulted in a decrease in redness of 8.4%, which was a significant change compared to baseline and the placebo group. The effect was also visible in macrophotographs of the skin of the test participants. The brightness of the skin had increased by 2.1% in the subjects who had used 2% Alpine Rose extract, which was a significant change compared to baseline and the control group.
After 28 days of treatment, skin elasticity had improved by 16.1%, a significant difference from baseline and the placebo group.
Another active ingredient used to fight zombie cells is an extract from Baikal hellebore (“SCUTALINE”). Both active ingredients represent a new generation of active ingredients that translate current research results into available active ingredients for cosmetic products.
Here you can find details of the active ingredients against zombie cells that have been available so far:
| Handelsname | INCI | Hersteller | Bemerkung |
|---|---|---|---|
| Alpine Rose Active | Rhododendron Ferrugineum Extract + Glycerin + Aqua | Mibelle AG Biochemistry | |
| Celyscence | Glycerin, Aqua, Silybum Marianum Extract | Clariant | |
| SCUTALINE | Scutellaria Baicalensis Root Extract | Biosil Technologies, Inc. |
Outlook
Zombie cells are significantly involved in the ageing process of the skin by inducing and accelerating inflammatory reactions and the degradation of the extracellular matrix. For the first time, senolytic activity has been demonstrated in vitro for a cosmetic active ingredient, an extract of organic alpine rose petals. In a clinical study with a placebo control group, alpine rose extract also reduced redness and increased skin elasticity.
This is an interesting new concept of equipping cosmetics with active ingredients against zombie cells. Cosmacon will be happy to help you turn these current research results into innovative cosmetic products. Please feel free to contact us.