Jump to content
Powered by

Telomeres and stem cells - Building blocks associated with ageing

Prof. Dr. Lenhard Rudolph, a well-known stem cell researcher at Ulm University, is investigating the relationships between telomeres, stem cell ageing and diseases. In the following interview with Walter Pytlik, BioRegion Ulm, Rudolph gives insights into state-of-the-art ageing research and its potential applications.

Numerous molecular theories attempt to explain the process of ageing. Is a molecular theory alone enough to understand the ageing process?

I am sure that molecular and cellular approaches provide explanations as to why and how organisms get older. However, it is necessary to bring together different theories. A single theory, for example one that focuses on DNA damage or the effect of free radicals on ageing, is not at all sufficient. We are far from being able to understand how the individual mechanisms interact, whether they enhance each other and eventually induce processes that go beyond the cell. Our research has shown that telomere shortening impairs the function of stem cells. But rather than being the result of shortening telomeres in the stem cells, this impairment is the result of their shortening in the stem cell niche.

Your Max Planck research group is investigating the ageing of stem cells. Is there any evidence that stem cells get older?

Stem cell researcher Prof. Dr. Lenhard Rudolph. (Photo: University of Ulm)
It has been shown in many stem cell populations that the stem cells (SC) gradually lose their function as they age. The majority of investigations have dealt with model organisms, in particular mice. Of course, it is a lot more difficult to transfer these examinations to humans. There are several reasons for this. Human SC are not available in the quantity required; it is also difficult to conduct functional studies with cell cultures. Far too little is still known about how SC are kept in cell culture. A standard method is to examine SC function by transplanting them into a model organism. However, it is known that human SC from bone marrow transplants gradually lose their function. In the treatment of leukaemias, problems are often experienced with bone marrow transplants, either that SC do not adhere properly, or that the patients contract dangerous infections. It is known that the age of a stem cell donor has a significant influence on the treatment outcome. From this it can be concluded, for example, that the function of haematopoietic SC decreases with age.

What is the role of stem cell ageing compared to other ageing theories?

It is known that the length of SC telomeres also shortens over time. Some SC, for example haematopoietic stem cells, express only limited amounts of telomerase (an enzyme that synthesises telomeres). The quantity of telomerase is therefore too low to maintain the stability of SC telomeres. Our research with mice has shown that the shortening of telomeres does indeed reduce stem cell function.

What is the relationship between telomere shortening and stem cell ageing?

It is known that the length of SC telomeres also shortens over time. Some SC, for example haematopoietic stem cells, express only limited amounts of telomerase (an enzyme that synthesises telomeres). The quantity of telomerase is therefore too low to maintain the stability of SC telomeres. Our research with mice has shown that the shortening of telomeres does indeed reduce stem cell function.

Is there a causal relationship between telomere shortening and ageing?

It is nowadays believed that telomere shortening is the reason why we age. We have shown in mice that telomere shortening impairs the regeneration of damaged tissue, the response to stress, hence resulting in the reduction of an organism’s life expectancy. There is evidence that this is also true for humans. In 60 to 75-year-olds, telomere length is associated with life expectancy; a healthy 60 to 75-year-old with shorter telomeres will probably have a shorter lifespan than a person of the same age with longer telomeres.

Some researchers believe that the telomere apparatus prevents cells from committing suicide or from becoming tumour cells. Senescence would then not lead to the death of a cell, but rather to the prolongation of a cell’s lifespan, a kind of self-protection. Is there sufficient knowledge about the molecular mechanisms of the telomere apparatus that would allow us to pharmacologically interfere with the telomerase enzyme?

Shortened telomeres (red) induce chromosomal damage and increase cancer risk. (Photo: University of Ulm/Rudolph)
The limitation of an organism’s lifespan is a protective mechanism against cancer. This tumour suppressor hypothesis is substantiated by findings that the telomerase enzyme is reactivated in more than 80% of all human tumours. The inhibition of this enzyme is a pharmacological starting point in the effort to impair tumour growth. Some pharmaceutical companies are already working on this issue. Other pharmacological substances are already in phase I and II of clinical testing.

It is also known that shortened telomeres increase the risk of cancer. Cancer risk is elevated in old tissue with very short telomeres. Tumour risk is also elevated in chronic diseases (e.g., liver cirrhosis), which promote telomere shortening. In this case, liver cirrhosis sufferers run a high risk of developing liver cancer. The shortening of the telomeres does not improve the tumour suppressor function; in contrast, cancer risk increases. All this is based on the assumption that young organisms have long telomeres. Cancerous cells lead to shorter telomeres in the cell clones and their growth is impeded. The ageing of whole organisms, in particular when the maximum biological age is reached, will lead to the shortening of telomeres in all proliferative tissues. This not only then impairs the proliferation of tumour cells, but also prevents the proliferation of normal cells. This in turn might also induce a tumour. All tumours in elderly people have a high rate of chromosomal instability. A tissue that no longer proliferates properly induces signals that attempt to create a maximum rate of tissue proliferation. The environment changes, and more cytokines and growth factors are released. This might lead to the proliferation of a malignant clone. Therefore, chromosomal instability is intrinsic to cells whereas the environment is the cause of the selection of malignant cells.

The telomeres are shortened in all organs as organisms age. Is there a correlation with chronic, degenerative diseases?

There is a correlation between many chronic diseases and telomere shortening. Liver cirrhosis is one such example. In a normal liver, the telomeres shorten slowly as the organism ages. In the case of chronic hepatitis, the cells proliferate more rapidly, which in turn leads to the more rapid shortening of the telomeres. The disease gradually develops into liver cirrhosis which eventually leads to liver failure. Another example is chronic inflammatory intestinal diseases where the telomeres of the intestinal epithelium become shorter and eventually lead to the loss of function of the intestinal epithelium and higher risk of cancer. There are many other such examples.

Are there further factors that limit the self-renewal of SC?

Yes, it is believed that there are other factors besides telomere shortening that have an effect on the self-renewal of SC. Researchers have discovered in bone-marrow transplanted mice that there are telomere-independent and telomere-dependent mechanisms that exhaust the colonisation ability of stem cells.

Have the molecular processes of telomere shortening been clarified? Is it known exactly when the SC receive the signal to stop proliferating?

It is known that telomere shortening eventually leads to telomere dysfunction, to the loss of the protective cap at the chromosome ends. This leads to the activation of DNA-damage signals, which leads to cell cycle arrest or apoptosis. Little is still known about this process in SC because SC are difficult to investigate. Over the last few years, our group has made a number of contributions to clarifying this process and has shown that the activation of p21 leads to the exhaustion of SC in response to telomere shortening. This means that the p21 signalling pathway is also important in SC and appears to lead to a loss of SC function when the telomeres lose their protective function.

Are there differences in telomere shortening in somatic cells and stem cells?

It is believed that the telomeres of somatic cells shorten quicker than SC telomeres. It is assumed that this is due to the fact that the telomerase enzyme of somatic cells is generally not active. This is completely different in haematopoietic SC. It is therefore assumed that the telomere activity in SC counteracts the shortening of telomeres, and that the telomeres shorten to a lesser degree per cell division round. However, the length of telomeres of SC nevertheless decreases significantly as an organism ages. From this it is deduced that the telomeres of SC shorten more slowly due to telomerase activity, but in old age they have reached a critically short length.

Does the knowledge of the cell-immanent response to telomere dysfunction allow conclusions to be drawn on stem cell ageing? Are there already therapeutic targets that would allow the improvement of stem cell function and enable the therapy of chronic diseases?

Over the last few years, we have identified two mouse genes that are activated in response to telomere dysfunction and then lead to SC dysfunction. These genes encode the exonuclease 1 and p21 proteins. SC function, seen in relation to telomere shortening and ageing, can be improved when these proteins are switched off. In ageing mice with short telomeres, this actually improved organ maintenance and also increased the lifespan of the mice without – and this is an important aspect – leading to greater tumour growth. The proof of principle showed that it is possible to inactivate control-point genes in ageing SC and hence improve their function.

What will enable the researchers to go from model organisms to human application?

The next logical step is the development of pharmacological substances that specifically target these structures. We have plans to work with the Max Planck Lead Discovery Centre and industrial partners to develop cell-based assay systems that will allow us to identify pharmacologically effective substances that target these structures.

Is anything known about areas outside of the cell that might affect the ageing of stem cells?

Micrographs of intestine cells
Adult stem cells with shortened telomeres in the intestine (Photo: University of Ulm/Rudolph)
Indeed, there is evidence that the response to telomere shortening, or in general to DNA damage, has an effect on the environment of SC, for example in the SC niche (consisting of endothelial cells and bone cells in the bone marrow). If these niche cells have dysfunctional telomeres, then this might result in the dysfunction of the niche cells and hence to dysfunctional SC. On the other hand, there is also evidence that the macro-environment changes: cell proteins with dysfunctional telomeres release certain substances. These proteins circulate throughout the entire body. They include growth factors, cytokines as well as non-classical secretory proteins that either directly influence the SC or influence the interaction of SC with their niche which then leads to SC dysfunction.

I’ve read a review which claimed that ageing cannot be measured due to the large number of ageing phenotypes. Now you have discovered proteins that actually determine the actual age of humans. What is the significance of this discovery for your research? How far are we from clinical application?

We identified these proteins in the supernatant of cells with telomere dysfunction and compared them with cells with long telomeres. We used a proteomics approach (the comparison of all proteins of a cell) to identify four proteins which are secreted by the cells in response to telomere dysfunction, but also in response to other DNA damage, for example damage caused by radioactive irradiation.

It is interesting to note that the quantity of these proteins increases in the blood serum as humans age. However, this increase does not just happen chronologically. It has been shown that the increase of these proteins is greater in old people with health problems than in old people who are healthy. This difference is once again very significant.

Therefore, we believe that these proteins are not pure chronological markers, but that there are differences between individuals. It is further assumed that a higher marker quantity actually reveals a higher biological age.

These markers might be useful for the treatment of old people in cases which require the tissue to regenerate, for example surgery. Studies involving biomarkers of ageing might actually be able to predict the benefit of such surgery. This would represent a huge clinical progress in the invasive therapy of old people.

I can also imagine another interesting application for these markers; for example in anti-ageing medicine, i.e. anti-ageing food supplements. People taking vitamins at the age of fifty will most likely only know in about twenty years’ time whether the vitamins have had any beneficial effect. Biomarkers of ageing might be able to give an immediate answer. For example, the effect of vitamins could be assessed using a group of volunteers, for example 70-year-olds with a higher quantity of specific ageing biomarkers, where one group receives a specific vitamin and the control group is given a placebo. The amount of biomarker would then tell us whether the consumption of the given vitamin arrests or even decreases biological ageing markers. I believe that this is of great interest for the food industry.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/telomeres-and-stem-cells-building-blocks-associated-with-ageing