ESOF2014: Young Scientists Fighting Age-related Diseases

(June 30th, 2014) The ineffectiveness of antibiotics and the spread of infectious diseases are to some extent manageable but there’s one health threat that cannot be escaped: Aging. George Garinis, Björn Schumacher, Lene Rasmussen and Gerald de Haan spoke about their projects for a healthy long life.



What causes us to get older and not only older but weaker? Our bodies accumulate little defects, lose energy and get ill in the end. For centuries, people have been looking for the key to immortality and, compared to 200 years ago, at least in the Western world, the average life span has doubled. But old age is only a pleasure if you are healthy and fit enough to enjoy life and are not a burden for society. During ESOF2014, four young scientists talked about their approaches to tackle the issue from different angles.

George Garinis from the Institute of Molecular Biology and Biotechnology (FORTH) travelled from Greece to Copenhagen to point out the importance of DNA damage and its accumulation with age due to defects of DNA repair mechanisms. Contradictory, this is caused by natural selection, as Björn Schumacher from the University of Cologne in Germany explains: "There is one cell type that doesn't age, and this is the germline. Our germline passes on our genetic information and every time an egg is fertilised, the biological clock is reset to zero. So there is immortality." But only in germline cells and not in somatic cells. Nature simply does not need them to keep life going. And this connects to the DNA repair pathways: "The repair is pretty good but not perfect. And because of the lack of selection for immortality of our somatic cells they don't have to be perfect, just good enough to keep us alive as much as we need."

Björn Schumacher also spoke about “longevity genes”. "There are genetic pathways that do influence ageing and which are linked to DNA repair pathways," he explained. This was firstly observed in C. elegans, where a single mutation in the daf-2 gene for insulin-like growth factor 1 (IGF-1) receptors doubled the lifespan of the worms. In mammals, it is more complicated but in extremely long living people, mutations are found in genes for IGF-1 receptors, too. As the name suggests, these receptors are responsible for body growth and mutant mice are smaller but live much longer.

The longevity pathways, too, are connected to DNA damage. Thus, it’s important to see the different outcomes of DNA damage: It leads to mutations and cancer, and to apoptosis and ageing. But there is a third outcome of DNA damage: "Even low levels of persisting DNA damage interfere with a part of the DNA metabolism and cells can respond to this by attenuating the somatotropic axis. This triggers the same longevity insurance pathway that we know already from the worms," Schumacher pointed out. This works through the enhancement of stress resistance and has another positive effect: Because it reduces cellular growth and survival, it antagonises cancer development. So, the damage accumulation is the driving force but genetic longevity insurance pathways respond to it and can counteract the consequences of genome instability, for example, by enhancing the tolerance towards DNA damage.

However, cancer and tissue degeneration are not the only aspect of ageing, we also lose energy and feel weaker and more tired, the older we get. Lene Rasmussen from the Center for Healthy Aging at the University of Copenhagen concentrates on this aspect. She looks at the energy-producing organelles in our body, the mitochondria. "What is giving us the biological energy, our bodies need to function, including maintaining these DNA repair systems George and Björn talked about? It is the mitochondria." Therefore it seems clear, that the accumulation of mitochondrial DNA (mtDNA) damage and mutations, leading to dysfunction of the organelles, result in cellular dysfunction and ageing. Lene Rasmussen sees three steps on the avenue of mitochondrial ageing research: "Firstly, we would like to find out how we can prevent mitochondrial dysfunction and decline during aging. Secondly, if we cannot prevent it, how can we restore the function again? And here we already know that exercise is a very good way because you restore the function and increase the number of mitochondria in your tissues. And lastly, there is a great focus on finding drugs to increase mitochondrial function."

Finally, a new emerging field gives us even more hope for a healthy future. It has to do with stem cells, the immortal cells, which replace all dying cells in our bodies. Unfortunately, even stem cells cease to function properly with advanced age, as Gerald De Haan from the European Research Institute for the Biology of Ageing, ERIBA, in Groningen, Netherlands, knows all too well. In his research, he combines stem cell research with epigenetics. He gave Lab Times an exclusive interview:


Lab Times: How can you specifically study the age-related mechanisms of stem cells?

De Haan: Basically, we purify stem cells from mice, where we have a very selective group of nascent stem cells, which we test functionally. We purify stem cells from an old mouse and from a young mouse, mix them 1:1 and transplant them in a recipient mouse. Then we see which group of cells wins because if they were equally fit you would think that half of the derived cells are from the old cells and half from the young. In our case, we look at blood stem cells, so blood derived from these stem cells. The young cells always win, so that suggests that there is an intrinsic problem with old stem cells.


Lab Times: Do you have any idea, which molecular or cellular mechanisms are responsible for this ageing of stem cells?

De Haan: No, we don't know what contributes to normal stem cell ageing. Of course, when you take mice, which are DNA repair- or telomerase-deficient, these stem cells behave very poorly. But this doesn't automatically give the answer to the normal ageing mechanisms. I don't believe there is a programme or a counting clock. I think it is just random. When a stem cell divides, the two daughter cells will accumulate mistakes, not necessarily on the DNA level but also the epigenetic level. So, with each and every division, these cells perform a little bit poorer. 


Lab Times: So, the stem cells lose their epigenetic marks, like histone methylation, acetylation etc?

De Haan: Yes, lose or alter. We would like to study the full epigenetic programme in two daughter cells and at the same level sequence the RNA transcriptome of these single cells. This is not doable at the moment, but I think in the next five years it will be. With this, we would be able to look at the full epigenetic profile of single cells. This would be very diverse, I bet. And there are not only a few genes that cause aging, I think there will be many. But if a cell would be able to maintain its epigenetic status that would definitely contribute to anti-aging. So, what we can do in our lab is: we overexpress certain epigenetic factors and then these cells self-renew much more efficiently. 


Lab Times: Do you think it is the same with other somatic cells?

De Haan: Yes, I think so, because stem cells are not very different from other cells in this respect.

Lab Times: And why do you work with stem cells?

De Haan: From an ageing perspective, stem cells are very interesting because they are defined by self-renewal, which is incompatible with ageing. And in ageing, you see that this self-renewal decreases dramatically. Self-renewal is also a characteristic of cancer. So in the end, cancer cells don't differentiate anymore and only proliferate. You could intervene in that process and induce differentiation by preventing self-renewal. And it is also interesting in terms of oncogenic mutations in young cells and in old cells because the same mutation can have different outcomes. Cancer that is initiated in someone old might be a different type of cancer than in someone young, yet the cancer results from the same oncogenic event.

Karin Lauschke

Photo: www.esof2014.org, Björn Schumacher, Gerald de Haan, Lene Rasmussen




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