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.
A number of biological quality control processes become faulty with age, and one of these is protein quality control. Proteins are the "molecular machines" in all cells; they are complex structures that have to reach proper folding states to become functional. A host of support proteins enable proper protein folding and numerous degradation pathways are in place to ensure protein quality control. This protein homeostasis network loses its function as organisms get older, and the toxic misfolding of proteins causes many age-related diseases. These include Alzheimer’s and Parkinson’s disease.
We are implementing a number of forward genetic screening approaches to identify mechanisms that modulate the rate of ageing. We then aim to understand the underlying biology using molecular and biochemical approaches. 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 vision is to first identify biological processes that modulate how organisms age and, second, to understand these at molecular detail. 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.
To address our research questions, we are using a number of biological tools: Our "work horse" is the model organism Caenorhabditis elegans that we use for genetic screens that aim to reveal novel genetic loci relevant for ageing. We then investigate these mechanisms at a molecular level and 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, biochemical approaches 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.