Rare diseases provide insights into the mystery of human aging

Berlin, 26.2.2019. "Infantile old men" and so-called "moonshine children" - in common parlance, impressive images are used for those affected by several complex clinical pictures caused by an inborn malfunction of DNA repair mechanisms that have hardly been researched until now. With Prof. Dr. Björn Schumacher from the CECAD Cluster of Excellence for Aging Research at the University of Cologne, one of the most distinguished researchers striving for a fundamental understanding of these processes received the Eva Luise Köhler Research Prize for Rare Diseases 2019, endowed with 50,000 euros. The award ceremony took place on February 26, 2019 in Berlin.

Environmental influences, such as UV light or tobacco smoke, but also quite ordinary metabolic by-products cause about ten thousand damages to the genetic material every day - in every single cell of the human body. Fortunately, early in evolutionary history, cellular repair systems, such as nucleotide excision repair (NER), emerged to remove damage that alters the double helix structure of DNA.

A member of Prof. Schumacher's staff in the laboratory of the CECAD Research Center. Photo: CECAD/3M2Film

"If these repair systems do not function properly due to certain congenital genetic defects, not only the cancer risk of the person increases significantly," explains renowned pediatric endocrinologist Professor Dr. Annette Grüters-Kieslich, Chairwoman of the Board of the Eva Luise and Horst Köhler Foundation for People with Rare Diseases, and adds: "The effects of these disease patterns - such as xeroderma pigmentosum (XP) or Cockayne syndrome (CS), which have hardly been researched yet - are absolutely dramatic in many respects for the mostly very young patients."

The young patients age as if in fast motion and die early

The skin of "moonlight children" - as XP patients were often called in the past because they have to avoid all UV radiation throughout their lives - reacts a thousand times more sensitively to UV radiation than that of healthy people. Without consistent protection, those patients often develop severe burns after only a short exposure to the sun and skin cancer in the first years of life.

An only slightly different mutation in another gene that repairs damage to the DNA causes Cockayne syndrome (CS), which is also very rare. It causes the children to age as in fast motion: even in the first few years of life, the "young olds" suffer from typical symptoms of old age, such as hardening of the arteries and a rapid decline in hearing and vision. The patients remain small and die before they reach their teens because there is currently no therapy beyond treating the accompanying symptoms.

View into the laboratory of Schumacher's team at the CECAD Cluster of Excellence in Cologne. Photo: CECAD/3M2Film

"To mitigate the dramatic effects of our fragile DNA, repair systems evolved early in evolutionary history," Professor Björn Schumacher explains. He points out that the study of genes with congenital defects in CS and XP has already provided his research group with a lot of insight into basic functioning of the cell: "Rare diseases give us insights into the mystery of human aging."

The researchers recreate the effects of the gene defect in the nematode model

In order to study NER disease mechanisms in vivo, Professor Schumacher's research group developed a nematode (C. elegans) as a model organism that carries the same genetic mutation which causes CS in humans. Such a simple animal model - after all, a 70 kg human has about 30 billion times more somatic cells than a nematode - is invaluable for research, especially into highly complex disease patterns.

The model organism showed that the malfunction of the NER repair mechanism does not lead to mutations which are passed on from cell division to cell division. Rather, the damage remaining in the genetic material impedes the reading of genes, a process essential for cell function. The cell reacts to the remaining DNA damage with a highly complex cascade of events at the molecular level, at the end of which it ceases its activity and dies. The body cannot develop, and tissues and organs lose their ability to function.

This year's research award winner Prof. Björn Schumacher. Photo: CECAD/3M2Film

"Using our nematode model, we were able to show that these damage response mechanisms run via specific signaling pathways that are controlled, for example, by insulin-like growth factors (IGFs). They are of central importance for aging - whether prematurely in CS or gradually in the course of the normal aging process. As part of our project, which is funded by the Eva Luise and Horst Köhler Foundation, we now want to take a closer look at how we can affect the signal chain therapeutically," Björn Schumacher is confident. In contrast to the highly complex mechanisms of nucleotide excision repair (NER), the signaling pathways can be therapeutically targeted by certain drugs. For example, scientists in his research group at CECAD were able to restore tissue function and delay aging even in nematode mutants that completely lacked NER repair mechanisms.

Initial therapeutic approaches

The identification of these damage response mechanisms provides new perspectives for the pharmacological treatment of progeroid inherited diseases for which no therapeutics are currently available, the laureate hopes: "Our research could become a basis for realistic and feasible therapies in the future."

The Eva Luise Köhler Research Award for Rare Diseases has been awarded for the twelfth time in collaboration with the Alliance of Chronic Rare Diseases (ACHSE) e. V..

The laureate

Professor Dr. Björn Schumacher studied biology at the University of Konstanz and Stony Brook University in New York and received his PhD from the Max Planck Institute of Biochemistry in Martinsried near Munich.

The molecular biologist is considered one of the most distinguished aging researchers worldwide. His research group at the CECAD Cluster of Excellence for Aging Research at the University of Cologne focuses in particular on nucleotide excision repair (NER), a mechanism responsible for detecting and repairing damage in genetic information. CECAD has been funded by the German federal and state governments since January 2019 in the third funding period of the Excellence Strategy and focuses on the fundamentals of various diseases of aging.

Pictures: CECAD
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