It is widely assumed that mitochondrial dysfunction and subsequent ROS (Reactive Oxygen Species) production are crucial players in ageing. However, the specific role of mitochondrial pathways in the onset and progression of degeneration and ageing is still unclear, as is the degree of interplay among organs in the ageing process. We hypothesise that impairing mitochondrial respiratory function leads to oxidative stress and ROS production. This induces DNA damage, inflammation and, ultimately, cell senescence and ageing.
We have developed mathematical models using differential equations to describe the corresponding signalling pathways. Further, our consortium has developed so-called conplastic mouse strains, i.e. a set of mouse models with defined and stable mutations of mitochondrial genes associated with respiration and ROS production to define the specific role of the different mitochondrial respiratory chain elements in the modulation of these pathways. These models are unique with respect to specificity and stability. Combining wet-lab and systems biology modelling approaches, we generate an advanced model of mitochondrial ageing describing ROS effects, which is iteratively improved. We hypothesise that cell senescence, tissue ageing and organismal ageing are not a linear function of ROS effects. Instead, these phenomena relate to each other by complex age-dependent interactions of ROS-induced signalling in different organs. Since neurodegenerative diseases, metabolic syndrome and cancer are major healthcare challenges, we investigate these as model systems of cellular, tissue and organ ageing. Organismic ageing will depend on dysfunctions of defined organs at specific time points in life linked to specific mutations in the mitochondrial proteins. We will address this challenge using a two-tier approach, including a. comprehensive cellular modelling and b. comparative model analysis. For the cellular modelling, data sets for each organ, mutation and time point will be generated using standardised experimental measurements, which then provide the input for the advanced mathematical models describing short-term ROS effects.
The output are modelling insights such as critical experimental parameters, differential pathway activation patterns and predicted mechanisms; they form the input for the next tier, a comparative analysis of modelling insights. This analysis will consider long-term ROS effects by forming mutation- and organ-specific similarity clusters and relating these to life span. Clustering will reveal the relative contribution (to the overall ageing process) of mutation/organ/tissue specific ageing at different developmental time points. The precise description of emergent cluster patterns will allow us to define predictors of ageing and open the perspective to identify specific markers and to develop tissue-specific ageing-protective interventions.
Two industrial partners will provide us with both technology platforms for visualisation of morphometric data as well as for monitoring respiratory function in tissue samples and will each contribute its own R&D project part.
Department of Medical Biochemistry and Molecular BiologyUniversity of Rostock
Department of Medical Biochemistry and Molecular Biology
University of Rostock
Institute for Biostatistics and Informatics in Medicine and Ageing Research
Faculty of Medicine
University of Rostock