Unraveling the molecular mechanisms of ageing

Damage to the DNA is a leading cause of ageing-related diseases and cancer. Recently, two EU projects, CodeAge and aDDRess, were initiated to find out more about the underlying molecular mechanisms

Ageing is strongly correlated not only with a general functional decline, but also with a host of human pathologies. It has been known for quite some time that chronic DNA damage may play a crucial role in the origin of certain diseases. Understanding the underlying molecular mechanism behind this process could be key to prolonging the length and extending the quality of human life.

The CodeAge project focuses both on the damage that results from a shortening of telomeres in cell division, and on the damage caused by interfering with normal DNA metabolism.

“UV lesions and helix-distorting chemical adducts are recognised and repaired by a multi-protein nucleotide excision repair complex comprising two pathways: global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER),” explains Dr. Björn Schumacher, principal investigator of the CECAD Initiative in Cologne, Germany, and CodeAge coordinator.

“Patients with defects in their GG-NER pathway, for example, are highly susceptible to skin-cancer-prone Xeroderma pigmentosum (XP), whereas defects in TC-NER give rise to premature aging disorders such as Cockayne’s syndrome and trichothiodystrophy. We are taking a closer look at both NER mechanisms to further investigate the genes and proteins involved.”

Telomeres are arrays of repetitive DNA sequences located at the ends of linear chromosomes in eukaryotic organisms. By compensating for incomplete DNA replication at chromosomal ends, they prevent a chromosome’s DNA from being eaten away. Progressive telomere shortening limits cell divisions and therefore protects against uncontrolled cell division in cancer. This tumour-protective consequence of telomere shortening, however, comes at the price of limited cell division that prevents tissue renewal and repair and therefore contributes to ageing. A better understanding of the pathways that enable cells to tolerate dysfunctional telomeres or to maintain their function is critical for understanding the processes behind cancer and ageing.

While CodeAge pursues the link between DNA damage and aging, aDDRess takes a more mechanistic view of nucleotide excision repair, base excision repair and homologous recombination.

“It’s a well-known fact that chromatin can have a major impact on these processes” says Professor George Garinis, group leader at the Institute of Molecular Biology and Biotechnology at the University of Crete and coordinating scientist of aDDRess.

He refers, for example, to Cockayne’s syndrome, which can be directly linked to mutations in the ATP-dependent chromatin-remodeling CSB protein essential for DNA repair: “The major question is how chromatin and chromatin conformation might impact the DNA damage responses.”

Although chromatin acts as a physical barrier to the detection and repair of DNA lesions, it is also a dynamic structure that can be modulated. For example, it is assumed that DNA damage can lead to local chromatin modifications and spatial restructuring, without which it would be impossible for repair proteins to access the DNA lesion. Addressing these dynamic changes is a multidimensional task, which starts from the supramolecular structure of chromatin and goes down to the excision of small bases. “Of course, the ultimate goal of aDDRess would be to translate our findings into a better understanding of certain disease processes,” says Garinis.

Using the right model system is half the battle. Both CodeAge and aDDRess are working with various model systems in yeast, Caenorhabditis elegans, human cells and mice to pursue complementary research approaches. In budding yeast, for example, telomerase is constantly expressed and telomere length is stable. However, telomerase can be deleted, giving yeast cells a life-cycle much like that of mammalian somatic cells: their telomeres shorten, they enter into a period of senescence, and at low rates cells recover from senescence using telomerase-independent mechanisms to maintain telomere length and function. David Lydall’s CodeAge team in Newcastle uses this system to identify genes that affect telomere-driven senescence in a genome-wide analysis.

By contrast to single-cell yeast, C. elegans is a simple organism composed of fewer than 1,000 somatic cells, including cell types characteristic of all metazoans such as muscle, nerve, intestine and skin. Particularly Schumacher’s team in Cologne and Nektarios Tavernarakis of the Institute of Molecular Biology and Biotechnology in Heraklion are using the nematode to answer the question of how DNA damage in actively growing tissue can distort the integrity of the genome. Moreover, investigating the post-mitotic cells of C. elegans may help find new pathways, which preserve tissue function when DNA damage accumulates with ageing.

Stem cell research is also part of CodeAge. Since stem cells are continuously proliferating throughout their lifetime, it is of great interest to explore the role of telomeres and telomerase in these cells. Lenhard Rudolph’s group at the Leibniz Institute of Age Research in Jena is studying their function in a telomerase-deficient mouse mode showing various stem-cell defects. By performing genetic screens in the hematopoietic system, the researchers want to find out which genes might be necessary to preserve stem-cell function, despite a shortening of telomeres. Finally, “to give us an idea as to whether our findings in mice can be transferred to humans, we aim to define biomarkers that can help us detect aging and age-related diseases in humans,” says Schumacher.

aDDRess and CodeAge combine advanced know-how in molecular genetics research, omics technologies, translational research and clinical application. A significant proportion of the expertise in both projects comes from medium-sized biotech companies. Biomedcode, for example, is a Greek contract-research organization with a unique collection of proprietary mouse models. Mosaiques diagnostics GmbH provides highly innovative clinical proteomics services and a database of naturally occurring human urinary peptides and proteins, which may serve as biomarkers for the diseases under investigation. Berlin-based ATLAS Biolabs GmbH, a leading provider of complex analyses in molecular genetics – including microarray-based genomic services, targeted sequence capture, next-generation sequencing (NGS) and high-level bioinformatics – will be responsible for the analysis of the NGS data collected in both projects. This task also includes the development of new strategies and bioinformatics tools for NGS data analysis and the identification of biomarkers of DNA damage.

The participation of medium-sized businesses can help the PhD students and young talents in the program to obtain professional experience in the industry. “Traditionally, junior researchers stay at universities or academic institutions while they are doing their doctoral thesis. After graduation, however, many of them will leave academic science to pursue a career in industry; we see it as a

major problem in most doctoral programs that they are not prepared to work in companies. CodeAge and aDDRess offer a complementary approach by giving young talents the opportunity to develop other prospects outside academia,” says Professor Peter Nürnberg of the Cologne Center for Genomics in Germany and CEO of ATLAS Biolabs. Im Rahmen der beiden EU-Programme wird sein Unternehmen zwei graduate students einstellen. The EU-funding will allow ATLAS Biolabs to hire two graduates working on the various aspects of bioinformatics in both projects.

Participants of both programs will therefore be offered several workshops on business issues, in addition to methodological and research-related workshops. These will deal with the most important issues involved in launching a start-up enterprise in the field of biotechnology or life sciences: How to achieve optimal patent protection? How to finance a spin-out and commercialize a business idea? Workshops are co-organized by the companies in the program, so that the young scientists learn the whole process of starting a business first-hand.

aDDRess and CodeAge are being funded for four years by the Marie Curie Initial Training Networks within the European FP7 program. The Marie Curie Initial Training Networks are open to young researchers who want to gain experience abroad in the private sector and to complete their training by participating in a joint European research project. The duration of research stays may vary, depending on the requirements of the scientific objective. The two projects involve a total of 22 research groups in 9 different European countries.

“Both projects cover related topics and provide great opportunities for excellent research. We are delighted to be receiving this EU funding and are sure both programs will benefit from each other,” George Garinis, aDDRess coordinator concluded.

Dr Katrin Mugele