Autophagy and Cellular Ageing
Ageing is described by a general decrease in cellular function over time. Eukaryotic cells have evolved numerous surveillance and quality control systems to detect, remove, and replace dysfunctional components to maintain cellular function. However, cellular functions do decline over cellular lifetime suggesting that cellular quality control systems are inherently limited in their capacity to counteract damage. Accumulating damages in turn might reduce the effectiveness of quality control systems causing a progressive loss of cellular health. Understanding the limitations of quality control systems and their dependence on cellular functions might reveal novel targets for intervention in order to improve and extend cellular and organismal health span.
Autophagy is a central quality control and stress response conserved in all eukaryotic cells. Autophagy allows cells to counteract stress conditions such as nutrient starvation or cellular damage by degrading portions of their cytoplasm. Defects in autophagy have been linked to the pathophysiology of a variety of human diseases and ageing. Evidence indicates that autophagy activity is positively correlated with longevity and that reduced autophagy shortens lifespan. Notably, autophagy capacity declines with age. Hence, working towards a comprehensive understanding of autophagy regulation will likely open up many new avenues for therapeutical intervention.
A hallmark of autophagy is the de novo formation of double-membrane vesicles termed autophagosomes (Fig. 1). Driven by the concerted action of a complex core autophagy machinery and a number of cellular processes, nascent autophagosomes encapsulate cytoplasmic cargoes of diverse size and nature and target them for lysosomal or vacuolar degradation and recycling. Cells have to carefully fine-tune the level of autophagy according to their current needs. However, we are just beginning to understand how cells integrate a multitude of information about their metabolic and functional state to elicit a stress-adapted autophagy response.
Our lab is interested in understanding the interrelationship of autophagy and the ageing process on a cellular level. To this end, our four overarching goals are (1) to elucidate the molecular mechanisms required for the core process of autophagy and its stress-specific adaptations, (2) to gain a system-wide understanding of the contextual requirements for cellular functions in maintaining autophagy capacity, (3) to achieve a comprehensive view on the mechanisms of cellular ageing, and (4) to determine the causal interrelation of changes in cell function and autophagy during ageing. Towards these goals, we employ a broad interdisciplinary approach to analyze yeast and mammalian cells including biochemistry, proteomics, cell and synthetic biology, functional genomics and system-wide, fully automated high-throughput systems.
Selected Publications Graef
Third party funding
- 2016-2020 | German Research Foundation (DFG)
Collaborative Research Centre SFB1218 “Mitochondrial Regulation of Cellular Function”, member