Research Group Leader – Principal Investigator, MPI for Biology of Ageing
Dr. Martin Denzel
Our research: Ageing is a complex process that is influenced by an organism’s genetic makeup and its environment. Why almost all organisms age is incompletely understood, and we know much less about potential ways to decelerate this process. A better understanding of the biology of ageing is particularly important as age-associated diseases are becoming more prevalent in increasingly older populations.
Proteins, the molecular machines in all cells, are complex structures that have to reach proper folding states to become functional. A host of support proteins ensure proper protein folding and numerous degradation pathways are in place to ensure protein quality control. This protein homeostasis network becomes faulty during ageing, and the toxic misfolding of proteins causes many age-related diseases. These include Alzheimer’s and Parkinson’s disease.
Our success: We are implementing a number of forward genetic screening approaches to identify mechanisms that modulate the rate of ageing. Past work has identified the metabolic hexosamine pathway as a novel regulator of protein quality control and organismal ageing. Now, we are analyzing the role of this pathway in depth using mammalian cells and mice. In addition, we are branching out to understand structural aspects of the hexosamine pathway regulation.
Our goals: Our vision is to identify biological processes that modulate how organisms age. This is a fascinating basic research problem as ageing biology is multidisciplinary in nature and thus contributes to a better understanding of various biological processes. At the same time, ageing research also provides insight into mechanisms of age-related diseases and can pave the way to interventions that can improve health as we age.
Our methods: In the Denzel lab we are investigating novel pathways that modulate the rate of ageing and that control protein quality control. To do this, we employ the model organism Caenorhabditis elegans in genetic screens that reveal novel genetic loci relevant for ageing. In addition, we investigate novel mechanisms in mammalian tissue culture. Finally, we use mouse models of neurodegeneration to test our findings in vivo. Use of this broad set of tools, including nematode transgenesis, the CRISPR/Cas9 system in tissue culture, as well as transgenic mouse models allows us to investigate ageing biology that is conserved across evolution and therefore likely to be relevant for human health.
Figure 1: Immunofluorescence image of a transgenic C. elegans animal that expresses the enzyme GFAT-1 fused to a fluorescent protein. GFAT-1 is the rate-limiting enzyme of the hexosamine pathway and increased function of improves protein quality control and extends lifespan.