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Systems biology: Ulm scientists' search for molecules that delay ageing

As stem cells get older, they gradually lose their ability to grow and reproduce. They accumulate damage and lose their ability to regenerate, thus knocking tissue homeostasis off balance. If stem cell ageing could be delayed or, even better, reversed, organs would work longer more effectively. The SyStaR research consortium is using systems biology methods and tools to investigate the mechanisms of age-dependent reduction of stem cell function and potential regeneration.

In order to make the dream of healthy and slower ageing come true, molecular mechanisms that limit stem cell function and hence organ maintenance need to be deciphered and biomarkers and molecular therapies need to be developed and transferred into clinical application. Fourteen groups of researchers from Ulm have joined forces in the cooperative research consortium SyStaR, which stands for “systems biology analysis of impaired stem cell function and regeneration during ageing”. SyStaR has been supported by the German Federal Ministry of Research and Education (BMBF) since autumn 2012 and will receive funding totalling 7.4 million euros up until 2016.

There is growing evidence that ageing does not always need to be a one-way street. © Pytlik

When supply ends

Adult stem cells are able to divide indefinitely and have so far been identified in 20 human body organs, including the bone marrow, blood, skin, liver and the brain, where they generate all cell types of the organ from which they originate throughout a person's life. Stem cells continuously replenish dying cells and regenerate highly active organs such as the liver, skin, intestines and bone marrow. The skin renews once a month, the intestinal mucosa every few days and the bone marrow produces around 300 billion blood cells a day. 

Over the past few years, Ulm University has earned an excellent reputation in adult stem cell research. Numerous scientists have achieved international visibility with research into ageing, regeneration and stem cells. Two years into its funding period, SyStaR has been evaluated and been given excellent feedback. Prof. Dr. Karin Scharffetter-Kochanek, medical director of the Department of Dermatology and Allergic Diseases at Ulm University Hospital and SyStaR spokesperson, pointed out that the researchers are making good inroads into systems medicine. 

The researchers from Ulm are specifically focussed on the Wnt, Notch and NF-κB signalling pathways, which control the self-renewal of stem cells, and they have already identified some molecules as the potential causes of stem cell ageing. Experimental data suggest that it is possible to modify, i.e. rejuvenate, the functions of organs such as the skin, blood and the intestines by modulating signal transduction pathways. Dr. Scharffetter-Kochanek further explains that the long-term goal would be to find a common denominator of tissue homeostasis in these organs. 

Many theories to explain stem cell ageing

Prof. Hans Kestler is contributing systembiologic expertise. © Pytlik

Many different factors and causes on the cell, tissue, organ and organismic levels determine the age of organisms. Many theories have been put forward, but they all only take into account either mechanistic (such as the theory put forward by the researchers from Ulm) or structural aspects of ageing. However, just as molecular and cellular ageing mechanisms are specific to cells, organs and organisms, there are species-specific mechanisms as well as mechanisms that exist in a broad range of different species and that have been conserved during evolution.

 

SyStaR studies stem cell ageing in several different species (yeast, Drosophila, mice) as well as looking into highly conserved signal transduction pathways. Doctors in geriatric hospital services contribute their knowledge of human ageing processes derived from organs such as the skin, liver, intestines, muscles, serum and blood to the project, and basic researchers data on age-associated molecular mechanisms (oxidative stress, genetic factors, DNA damage and asymmetric cell division). 

 

“Short-lived and well characterised model organisms such as yeast, fruit flies and mice help scientists to study human ageing processes. Researchers seeking to transfer molecular ageing mechanisms from model organisms to human ageing models require a high level of expertise in systems biology. That said, Hans Kestler (currently professor of bioinformatics and systems biology at the University of Jena and head of the research group “Bioinformatics and Systems Biology of Ageing” at the Leibniz Institute for Age Research – Fritz Lipmann Institute) is one such researcher and is the key figure in SyStaR. 

An ageing model that pools all existing knowledge

Old haematopoietic stems are characterised by larger amounts of the protein Wnt5a (green). Cell nuclei are shown in blue. © C. M. Florian / Uni Ulm

Kestler relies on time-dependent models that reflect the dynamics of processes, i.e. age-dependent alterations of the signalling networks on the cellular and intercellular level. Kestler explains that the Boolean network, which is one of the simplest dynamic networks that exist, is suitable for modelling larger entities such as interacting signalling cascades. Kestler explains: “We want to develop a model that takes into account all currently available knowledge.”

 

SyStaR is very much focussed on studying a broad range of age-specific clinical samples (wound healing, skin, brain, intestines), developing pathway models and comparing them with human gene expression patterns. This enables the researchers to identify signalling pathways in humans and mice that are specifically associated with ageing. The data are processed in an iterative process, which means that human biopsies/clinical samples are repeatedly compared with experimental data obtained with model organisms and with literature data and subsequently adjusted. 

 

The team of researchers led by Prof. Dr. Hartmut Geiger have already made discoveries that have the potential to contribute to the development of regenerative medicine applications. They have discovered that the activity of the small RhoGTPase Cdc42 increases with age – both in the blood, liver and brain cells of mice and in human blood cells. The researchers showed in genetically modified mice that elevated Cdc42 activity in aged haematopoietic stem cells affects cellular organisation, resulting in the ageing of the haematopoietic stem cells.  

Prof. Geiger, Director of the Institute of Molecular Medicine and Stem Cell Ageing. © University of Ulm

Another discovery may well lead to even greater clinical success: a pharmacological compound (CASIN) was shown to inhibit the activity of the Cdc42 protein, resulting in the restoration of the cellular organisation of the haematopoietic stem cells and functional rejuvenation of aged HSCs. Stem cell ageing has long been considered irreversible. However, the researchers from Ulm identified Cdc42 activity as a pharmacological target for ameliorating the ageing of stem cells, and thus making it possible to reverse some aspects of immunosenescence. The findings of the researchers from Ulm thus cast doubt on the doctrine that ageing is a one-way street. 

Ageing blood cells reduce the efficiency of the immune system 

There is growing evidence that the ageing of haematopoietic stem cells directly affects immunosenescence, i.e. the gradual deterioration of the immune system. Deterioration of the immune system is considered a major contributory factor to the increased susceptibility to infection, autoimmunity, anaemia, vaccine failure or cancer (leukaemia) among the elderly. Extrinsic factors such as circulating cytokines and factors found in the direct stem cell environment (niche) along with regulatory epigenetic networks suggest that interconnected mechanisms jointly promote the ageing of haematopoietic stem cells, and hence immunosenescence. A systems biology approach such as the one being pursued by SyStaR has the potential to identify the major causes and factors that contribute to stem cell ageing, as well as study the effects of stem cell ageing. At present, Geiger’s and Kestler’s teams are working on the development of an immunosenescence mouse model.

Prof. Karin Scharffetter-Kochanek © University Hospital Ulm

In the meantime, researchers led by developmental biologist Prof. Dr. Michael Kühl and Prof. Dr. Karl Lenhard Rudolph (formerly at Ulm University, now at the Leibniz Institute for Age Research in Jena) have provided experimental evidence in mice that the modulation of canonical Wnt signalling might be “a novel therapeutic target to influence the survival of non-transformed stem cells and possibly also of tumour stem cells in response to DNA-damaging agents” (Tao 2015). 

Long-term funding required 

The researchers from Ulm believe that the study of the molecular and cellular ageing mechanisms could potentially treat age-related diseases. Given demographic developments, it seems plausible that the long-term funding of this young, dynamic as well as costly research area would make economic sense. Karin Scharffetter-Kochanek therefore criticises the decision made by Baden-Württemberg Stiftung, which has funded stem cell research for around ten years, to terminate funding at a time when demographic development provides enough reasons for continuing the funding of stem cell research. 

References:

 

Florian MC, et al. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell aging. Nature 2013 November 21;503(7476):392-396. doi: 10.1038/nature12631.

Geiger H, et al. The ageing haematopoietic stem cell compartment. Nature Reviews Immunology 2013;13:376-389. doi: 10.1038/nri3433.

Tao S, et al. Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage. EMBO J 2015 Jan 21. doi: 10.15252/embj.201490700.

Fukada S, et al. Adult stem cell and mesenchymal progenitor theories of aging, Front Cell Dev Biol 2014;2:10. doi:19.3389/fcell.2014.00010.

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