Stem cells are cells that exhibit little to no differentiation. If we translate this somewhat dry, scientific formulation, we recognize the potential of stem cells. Stem cells can form new cells, from skin to muscle to liver cells. They are like a Swiss army knife, equipped with everything a new cell needs. And that is what makes them so unique in the body. Another analogy would be the joker card in a game. You can always use this one.
Stem cells and their potential have long been known in medicine. They are already being used successfully to treat some diseases, such as leukemia. In this article, however, we will also show you that there are different types of stem cells. As we age, it seems that stem cells can no longer work as effectively as they used to, which is why stem cell depletion has been included as one of the Hallmarks of Aging. We show you the background, explain what stem cell niches are and why there is "stem cell tourism".
Stem cells - less is not more
The decline in the ability of tissues to recover is one of the most obvious features of ageing. Let's take a look at blood formation (hematopoiesis), which decreases with age. This leads to a lower production of immune cells that can adapt to ever-changing threats. Experts use a familiar term to describe this phenomenon: immunosenescence. This can result in anemia or malignant diseases of the bone marrow .
Researchers observed this functional "stem cell attrition" in mice at more or less all locations in the body where stem cells are located. These include the forebrain, bones and muscle fibers. Everywhere there, old or dead cells can no longer be adequately replaced by new cells.
Studies carried out on aged mice have provided further insights in this direction. There, scientists recorded a decrease in cell cycle activity in hematopoietic stem cells. This is related to the accumulation of DNA damage (see genomic instability) and to the inhibition of the cell cycle (see cellular senescence) by the protein p16INK4a , which we already know about. Telomere shortening (see telomere attrition) is also an important cause. However, these are all just examples of a much bigger picture of what causes a functional decline in the stem cell population.
Do we simply have too few stem cells in old age?
The obvious conclusion from the results of the studies should therefore be: The number of stem cells decreases with age. But is that even true?
Not quite, if you take a closer look at the stem cells, the picture becomes a little more complicated. First of all, you need to know that there are differently potent stem cells. Probably the most potent stem cell is the one from which we all originated: The zygote (quick note: a zygote is the fusion of an egg cell with a sperm cell)
Stem cells are organized somewhat differently in our adult body, mostly in the form of so-called stem cell niches. These are located in different places, depending on where they are needed. Our skin has several stem cell niches, as this is where the new cells mature from. But our organs, such as the liver, lungs and intestines, also have stem cell niches. These stem cell niches appear to be particularly affected in old age.
Stem cell niches - the site of ageing
Let's take the skin as an example. At a young age, you have a large depot of functional stem cells in the niche. These ensure that your skin renews itself quickly. These stem cell niches play a particularly important role in the case of injuries. However, not all stem cells in this niche are the same. Some are particularly industrious and make a major contribution to cell renewal, while others are rather sluggish and contribute little to wound healing.
What happens in old age? It seems that the total number of stem cells does not change much. However, the particularly hard-working ones are increasingly missing, so that the performance of the stem cells in their niche decreases. Stem cells can also fall into a kind of senescence in which they can hardly be activated.
Under the microscope, it looks as if there are enough stem cells, but in reality they are exhausted and can no longer keep up with production. The result. If we injure ourselves in old age, there are fewer hard-working stem cells and the wound takes much longer to heal.
Too few stem cells - the obvious solution is too simple
So we have our solution. We need more functional stem cells so that we can renew our bodies. Unfortunately, it's not quite that simple. Excessive stem cell activity has been associated with faster ageing. This finding was convincingly demonstrated in an experiment with intestinal stem cells of fruit flies (Drosophila). Increased division of stem cells led to premature ageing
And when cells divide uncontrollably, we have another name for it: cancer
Let's go back to INK4a (see cellular senescence) and IGF-1 (see deregulated nutrient measurement). A paradoxical effect has been described for both parameters in the course of life. An increase in INK4a drives cells into cell cycle arrest - senescence occurs. A decrease in IGF-1 in serum is also associated with a decline in cell division. Both of these processes occur during normal ageing, but with positive intent. Namely, they reflect our body's attempt to maintain the integrity of stem cells.
Did you know In the Hallmarks of Aging there is frequent mention of free oxygen radicals. The so-called ROS play a dual role here. At a young age, they can be beneficial for us, while an excess of ROS can destroy our DNA and proteins. In the same way, ROS affect stem cells. Too much of these radicals can potentially contribute to stem cell exhaustion.
Our body tries to prevent this mainly through the production of glutathione . If you want to know more about this, then take a look at our article on GlyNAC . We also explain why it is better not to substitute glutathione and what the amino acid glycine has to do with the topic.
GlyNAC is a promising molecule when it comes to cellular energy and also biological age.
FGF2 - a new starting point for exhausted stem cells
In the search for ways to reactivate stem cells for our benefit, research has focused on the protein FGF2. This is a growth factor for connective tissue cells. If the FGF2 level in the body is high, this leads to exhaustion in aged stem cells and thus to a reduction in their ability to recover.
The good news is that suppressing this signaling pathway prevents this condition. This is therefore a possible therapeutic strategy to combat stem cell exhaustion.
How can we strengthen stem cells?
Let's take a step back from basic research and look to the future. We now know that our stem cells are no longer as efficient in old age. But where does this come from? What causes our stem cells to age?
One possible explanation is provided by a somewhat bizarre experiment, which we also discussed in the 5th Hallmark of Aging. If you sew two mice together, one young and healthy, the other old and sick, you get a so-called parabiosis. Interestingly, the researchers found that the stem cells in the cell niches of the brain and liver were significantly rejuvenated in the old mice.
These results can also be reproduced by injecting old mice with the blood of young mice, which suggests that there was no exchange of stem cells, but rather that molecular signals existin the blood of the young mice that make the stem cells younger again. Which ones, that remains the question.
Did you know Such parabiosis experiments always cause a big stir in the press (see z.B. Bryan Johnsonself-experiment in which he has his son's blood plasma given to him). Such actions rightly raise major ethical concerns. Blood transfusions are not without risk and the "source of eternal youth" will certainly not be found in having young blood infused. It will be more interesting to find out which exact signaling pathways in young blood are responsible for the renewal of stem cells. This could then be used to design new therapy methods in the future.
Are there not other ways?
Luckily, young blood is not the only way to revitalize old stem cells. Sport seems to be a proven way to get stem cells active again. In addition fastingimproved the function of intestinal and muscle stem cells in animal models .
The effect of fasting is probably due to the regulation of various signaling pathways, mainly the IGF-1 and the mTOR pathway. It has also been shown that fasting mimetics, which act precisely via this molecular axis, also have positive effects on stem cells.
Influencing the stem cells with drugs
Finally, possible drug interventions to improve stem cell function were also on the research agenda. Scientists were particularly interested in the mTOR inhibitor rapamycin - an old acquaintance. This molecule exerts its effect by influencing proteostasis and by measuring energy signals. Based on these two mechanisms, studies have improved stem cell function in the skin, the hematopoietic system and the intestine.
These findings once again demonstrate the difficulty of unraveling the molecular basis for the anti-aging activity of rapamycin. It also highlights how interconnected the hallmarks of ageing are.
In addition to rapamycin, the pharmacological inhibition of CDC42 is also worth mentioning. Human cells in the senescence stage could thus be rejuvenated. Overexpression of CDC42, which is involved in cell cycle control among other things, was also detected in a certain type of lung cancer.
Stem cell therapy - beware of false promises
As we have seen, stem cells are potent helpers in the fight against ageing. If we can find out how to restore this natural resource to its full power, then many new possibilities are open to us.
It is precisely with this hope that there are (unfortunately) some black sheep who want to make a lot of money. In some regions of the world, z.B. in the Caribbean, stem cell therapy is being advertised. From improved wound healing to cancer therapy - the promises are often great, but the reality is often sobering. The FDA, the US Food and Drug Administration, has even issued an official warning against such scams.
Stem cells and aging: A question of time, not of means
The depletion of stem cells is an intrinsic consequence of age-related damage in cells. It is not wrongly assumed that this process is one of the main causes of ageing in our body. Ultimately, practically all the characteristics of ageing that we have learned about to date lead to stem cell exhaustion. Recent studies provide a promising foundation for the hypothesis that rejuvenation of stem cells can reverse ageing at the organismal level.
Are these findings a kind of basis for a time machine back to biological youth? Even if the idea is appealing to some, there is currently still too little evidence for this. In any case, massive investments are being made in the field of stem cell research compared to the other Hallmarks.
Stem cell therapies have been ubiquitous for years and have led to drastic improvements in the treatment of diseases such as leukemia. In addition, stem cells are said to have enormous potential in the field of transplant medicine.
It is therefore less a question of means than a question of timeuntil the results of stem cell research are transferred to the topic of anti-ageing and healthspan. Perhaps in future we will no longer have to worry about how to "restore" if we can also "preserve".
The next article in this series deals with the ninth hallmark of ageing: Changed intercellular communication.
