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. New cells can form from stem cells, ranging from skin to muscle to liver cells. They are like a Swiss Army knife, equipped with everything a new cell needs. And that makes them so unique in the body. Another analogy would be the joker card in a game. You can always use it.
In medicine, stem cells and their potential have been known for some time. They are already being successfully used in some diseases, such as leukemia. However, in this article, we will also show you that there are different types of stem cells. With age, it seems that stem cells can no longer work as effectively as they used to, which is why stem cell exhaustion has been recognized as one of the Hallmarks of Aging. We will 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 recovery ability of tissues is one of the most obvious features of aging. Let's take a look at blood formation (hematopoiesis), which decreases with age. This circumstance leads to a lower production of immune cells that can adapt to the ever-new threats. The scientific community uses a term we are familiar with to describe this phenomenon: immunosenescence.As a result, it can lead to anemia or malignant diseases of the bone marrow .
This functional "stem cell attrition" was observed by researchers in mice at more or less all locations in the body where stem cells are located. These include, for example, the forebrain, bones, or muscle fibers. In all these places, old or dead cells can no longer be sufficiently replaced by new cells.
Studies conducted on aged mice 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 already known protein p16INK4a . The shortening of telomeres (see telomere attrition) is also an important cause. However, all of this is just examples of a much larger picture of what causes a functional decline of the stem cell population.
Do we simply have too few stem cells as we age?
The obvious conclusion from the results of the studies would be: As we age, the number of stem cells decreases. But is that really true?
Not entirely, as a closer look at the stem cells makes the picture a bit more complicated.To do this, you first need to know that there are different potent stem cells. The most potent stem cell is the one from which we all originated: The zygote (a brief note: A zygote refers to the fusion of an egg cell with a sperm cell)
In our adult body, stem cells are organized somewhat differently, 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 new cells mature from here. But our organs, such as the liver, lungs, or intestines, also have stem cell niches. It seems that these stem cell niches are particularly affected in old age.
Stem cell niches – the place of aging
Let’s take the skin as an example. In young years, you have a large depot of functional stem cells in the niche. These ensure that your skin renews itself quickly. Especially in the case of injuries, these stem cell niches play a special role. Now, not all stem cells in this niche are the same. Some are particularly diligent and contribute significantly to cell renewal, while others are rather sluggish and contribute little to wound healing.
What happens in old age? It seems that the overall number of stem cells does not change significantly. However, the particularly diligent ones among them are increasingly missing, so that the performance of the stem cells in their niche declines.Stem cells can also enter a state of senescence, in which they are hardly activatable.
Under the microscope, it looks like there are enough stem cells present, but in reality, they are exhausted and can no longer keep up with production. The result. When we injure ourselves in old age, there are fewer active stem cells available, and wound healing takes significantly longer.
Too few stem cells – the obvious solution is too simplistic
So we have our solution. We need more functional stem cells to renew our body. Unfortunately, it is not that simple. Excessive activity of stem cells has been associated with faster aging.This insight was convincingly demonstrated in an experiment with intestinal stem cells from fruit flies (Drosophila). An increased division of stem cells led to premature aging.
And when cells divide uncontrollably, we have another name for that: cancer
Let’s remember back to INK4a (see cellular senescence) and IGF-1 (see deregulated nutrient sensing). A paradoxical effect has been described for both parameters over the course of life. An increase in INK4a drives cells into a cell cycle arrest – leading to senescence. Likewise, a decrease in IGF-1 in serum is associated with a decline in cell division capacity. Both processes occur during normal aging, but happen with positive intent.They reflect our body's attempt to maintain the integrity of stem cells.
Did you know? In the Hallmarks of Aging there is often mention of free oxygen radicals. The so-called ROS play a dual role. In young age, they can be beneficial for us, while an excess of ROS can destroy our DNA and our proteins. Similarly, ROS affect stem cells. Too many of these radicals can potentially contribute to stem cell exhaustion.
Our body mainly tries to prevent this through the formation of glutathione .If you want to know more about it, feel free to check out our article on GlyNAC . There we also explain why one should better not supplement 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 target for exhausted stem cells
In the search for ways to reactivate stem cells to our advantage, research has focused on the protein FGF2 . It is a growth factor for connective tissue cells.If the FGF2 level in the body is high, it leads to exhaustion in aged stem cells and thus to a limitation of recovery ability.
The good news is that suppression of this signaling pathway prevents this condition. This represents a potential therapeutic strategy to combat stem cell exhaustion.
How can we strengthen stem cells?
Now let's move away from basic research and take a look at the future. We now know that our stem cells are not as efficient in old age. But where does this come from? What causes our stem cells to age?
A possible explanation is provided by a somewhat bizarre experiment that we have already discussed in the 5th Hallmark of Aging.When you sew two mice together, one young and healthy, the other old and sick, you get a so-called parabiosis. Interestingly, researchers found that in the old mice, the stem cells in the brain's niches and in the liver were significantly rejuvenated.
These results can also be reproduced when old mice are injected with the blood of young mice, suggesting that there was no exchange of stem cells, but rather that there are molecular signals in the blood of young mice that make the stem cells younger again. Which ones, remains the question.
Did you know? Such parabiosis experiments always cause a stir in the press (see z.B. Bryan Johnson Self-experiment in which he receives his son's blood plasma). It is rightly pointed out that such actions raise significant ethical concerns. Blood transfusions are not without risk, and the "source of eternal youth" will certainly not be found in infusing young blood. It becomes more interesting to find out which exact signaling pathways in young blood are responsible for the renewal of stem cells. This could lead to the development of new therapeutic methods in the future.
Are there not other ways?
Fortunately, young blood is not the only way to rejuvenate old stem cells. Exercise seems to be a proven means to reactivate stem cells.Furthermore, fasting improved the function of intestinal and muscle stem cells in the animal model. The effect of fasting is likely due to the regulation of various signaling pathways, primarily the IGF-1 and mTOR pathways. It has also been shown that fasting mimetics, which act precisely through this molecular axis, have positive effects on stem cells. Pharmacological influence on stem cells Lastly, possible pharmacological interventions to improve stem cell function were also on the research agenda. In this context, scientists were particularly interested in the mTOR inhibitor Rapamycin – an old acquaintance.This molecule exerts its effect through the influence on the proteostasis and through the measurement of energy signals. Based on these two mechanisms, studies have shown that the stem cell function in the skin, in the hematopoietic system, and in the gut can be improved.
These findings once again highlight the challenging endeavor of unraveling the molecular foundations for the anti-aging activity of rapamycin. Furthermore, it makes clear how interconnected the characteristics of aging are with each other.
In addition to rapamycin, the pharmacological inhibition of CDC42 is also noteworthy. Human cells in the senescent stage could be rejuvenated as a result.An overexpression of CDC42, which is involved in the control of the cell cycle, has also been detected in a specific type of lung cancer.
Stem cell therapy – Beware of false promises
As we have seen, stem cells are potent helpers in the fight against aging. If we can find out how to restore this natural resource to its full potential, many new opportunities will be open to us.
Unfortunately, with this hope, there are some black sheep who want to make a lot of money from it. 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 grand, but the reality is often sobering.The FDA, the American authority for drugs, has even issued an official warning against such fraud cases.
Stem Cells and Aging: A Matter of Time, Not a Matter of Means
The depletion of stem cells is an inherent consequence of age-related damage in cells. It is not unjustly assumed, that this process is one of the main causes of our body's aging . After all, practically all the characteristics of aging that we have learned about so far culminate in the depletion of stem cells. Recent studies provide a promising foundation for the assumption that the rejuvenation of stem cells can reverse aging at the organism level.
Are these findings a kind of basis for a time machine back to biological youth? Even though the thought is appealing to some, there are currently still too few clues for that. In any case, compared to the other hallmarks in the field of stem cell research, massive investments are being made.
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 attributed enormous potential in the field of transplantation medicine.
It is therefore less a question of means than a question of time until the results of stem cell research are transferred to the topic of anti-aging and health span. Perhaps in the future we will no longer have to think about how to "restore" when we can also "maintain."
In the next article of this series, we will discuss the ninth hallmark of aging: Altered intercellular communication.
