Stem cells are cells that show 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’s what makes them so unique in the body. Another analogy would be the joker card in a game. You can always use these.
Stem cells and their potential have been known in medicine for a long time. They are also already being used successfully for some diseases, such as leukemia. In this article we will also show you that there are different types of stem cells. As we age, it appears that stem cells can no longer work as effectively as they once did, which is why stem cell exhaustion has been included as one of the Hallmarks of Aging. We will show you the background, explain what stem cell niches are and why “stem cell tourism” exists.
Stem cells – less is not more
The decline in the ability of tissues to recover is one of the most obvious features of aging. Let’s look at blood production (hematopoiesis), which decreases with age. This circumstance leads to a lower production of immune cells that can adapt to ever-changing threats. Experts use a term we know to describe this phenomenon: Immunosenescence. As a result, anemia or malignant diseases of the bone marrow can occur.
Researchers observed this functional “stem cell abrasion” in mice in more or less all places in the body where stem cells are located. These include, for example, the forebrain, bones or muscle fibers. This means that everywhere old or dead cells can no longer be adequately 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 together. The shortening of telomeres (see Telomere abrasion) is also an important cause. However, all of these are just examples of a much larger picture of what causes functional decline in the stem cell population.
We simply don't have enough stem cells as we get older?
The obvious conclusion from the results of the studies would have to be: the number of stem cells decreases with age. But is that actually true??
Not quite, when you take a closer look at the stem cells the picture becomes a little more complicated. To do this, you first need to know that there are stem cells with different levels of potency. Probably the most potent stem cell is the one from which we all emerged: The Zygote (short note: A zygote is the fusion of one egg cell with another sperm)
In our adult body, stem cells are organized somewhat differently, usually in the form of so-called stem cell niches. These are located in different locations depending on where they are needed. Our skin has several stem cell niches because this is where the new cells mature. But our organs, such as the liver, lungs and intestines, also have stem cell niches. Exactly these stem cell niches are apparently particularly affected in old age.
Stem cell niches – the site of aging
Let's take 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 special role, especially in the event of injuries. Now, not all stem cells in this niche are the same. Some are particularly hard-working and contribute particularly to cell renewal, while others are rather sluggish and contribute only little to wound healing.
What happens as we get older? It seems as if the total number of stem cells doesn't change much at all. However, the particularly hard-working ones are increasingly missing, so that the performance of the stem cells in their niche is declining. Stem cells can also enter a type of senescence in which they are difficult to activate.
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 as we get older, there are fewer hard-working stem cells and wound healing takes much longer.
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 was associated with faster aging. This finding was convincingly demonstrated in an experiment with intestinal stem cells from fruit flies (Drosophila). Increased division of stem cells resulted in premature aging.
And when cells divide uncontrollably, we have another name for it: cancer
Let's think back to INK4a (see cellular senescence) and IGF-1 (see deregulated nutrient sensing). A paradoxical effect over the course of life has been described for both parameters. A increase in INK4a drives cells into cell cycle arrest - senescence occurs. Likewise, a decrease in IGF-1 in the serum is associated with a decline in cell division ability. Both processes occur during normal aging, but with positive intentions. They reflect our body's attempt to maintain the integrity of the 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. At they can be beneficial to us, while an excess of ROS can destroy our DNA and proteins. ROS have the same effect on stem cells. Too much of these radicals can potentially contribute to stem cell exhaustion.
Our body tries to prevent this mainly through the formation of glutathione . If you want to know more about it, please take a look at our article about GlyNAC. We will also explain to you 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 biological age.
FGF2 – a new starting point for exhausted stem cells
In the search for ways to reactivate the stem cells to our advantage, research has looked at 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 a limitation in the ability to recover.
The good news is that suppressing this pathway prevents this condition. This is therefore a possible therapeutic strategy to combat stem cell exhaustion.
How can we strengthen the stem cells?
Let's now step away from basic research and take a look at the future. We now know that our stem cells are no longer as efficient as we get older. 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 also saw in the 5th century. Hallmark of Aging discussed. 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 in the old mice the stem cells in the cell niches of the brain and liver were significantly rejuvenated.
These results can also be reproduced by injecting old mice with the blood of young mice, which suggests that there was not an exchange of stem cells, but rather that in the blood of the young ones Mice molecular signals exist that make the stem cells younger again. Which one, that still remains the question.
Did you know? Such parabiosis experiments always cause a great stir in the press (see e.g.b Bryan Johnson Self-experiment in which he has his son's blood plasma given to him). Major ethical concerns are rightly raised about such actions. 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 ensure the renewal of stem cells. This would then make it possible to design new therapy methods in the future.
Aren't there other ways?
Fortunately, young blood is not the only way old stem cells can be strengthened again. Sport seems to be a proven means of getting the stem cells active again. In addition, fasting improved the function of intestinal and muscle stem cells in animal models.
The effect of fasting probably lies in the regulation of various signaling pathways, mainly the IGF-1 and the mTOR pathway. It was also shown that fasting mimetics, which work precisely via this molecular axis, also have positive effects on the stem cells.
Drug influence on stem cells
Last but not least, 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 friend. This molecule exerts its effect by influencing the proteostasis and by measuring energy signals. Based on these two mechanisms, studies have shown that the stem cell function in the skin, the hematopoietic system and the intestine has been improved.
These findings once again highlight the difficult task of unraveling the molecular basis for the anti-aging activity of rapamycin. It also makes clear how interconnected the hallmarks of aging are.
In addition to rapamycin, the pharmacological inhibition of CDC42 is also worth mentioning. Human cells in the senescence stage could 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 aging. If we can figure out how to restore this natural resource to full strength, then many new possibilities will open up to us.
It is precisely with this hope that there are (unfortunately) some black sheep who want to make a lot of money with it. In some regions of the world, e.g.b in the Caribbean, stem cell therapy is advertised. From improved wound healing to cancer therapy – the promises are often great, but the reality is often sobering. The FDA, the American drug authority, has even issued an official warning about such fraud.
Stem cells and aging: question of time, not question of means
Stem cell exhaustion is an inherent consequence of age-related damage to cells. It is not wrongly assumed that this process is one of the main causes of aging in our body. Ultimately, virtually all of the hallmarks of aging that we have learned to date result in stem cell exhaustion. Recent studies provide a promising foundation for the assumption that rejuvenation of stem cells can reverse aging at the level of the organism.
Are these findings a kind of basis for a time machine back to being biologically young? Even if the idea is attractive for some, there is currently too little evidence for it. In any case, compared to the other Hallmarks, massive investments are being made in the field of stem cell research.
Stem cell therapies have been ubiquitous for years and have led to dramatic improvements in the treatment of diseases such as leukemia. In addition, stem cells are said to have 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. Maybe in the future we won't have to worry about how to "restore" if we can also "preserve".
The next article in this series will focus on the ninth hallmark of aging: Altered intercellular communication.
