Ageing is a complex physiological process that affects almost all species, including humans. Despite its importance for all of us, the biology of ageing is insufficiently understood. To uncover the molecular underpinnings of ageing, I am performing an interdisciplinary research program that will identify and investigate metabolic and genetic regulators of ageing. Progressive loss of cellular homeostasis causes ageing and an age-associated decline in protein quality control has been implicated in numerous diseases, including neurodegeneration. This link between ageing and disease demonstrates the importance of basic research into the biology of ageing. On the one hand, this research offers new insights into fundamental biological processes. On the other hand, a deep understanding of biological underpinnings of the ageing process will open up new ways to address underlying causes for many diseases that affect Western societies.
Seeking for ways to improve protein quality, I have identified a novel longevity pathway in Caenorhabditis elegans. In a forward genetic screen, I found a link between metabolites in the hexosamine pathway and cellular protein quality control. Hexosamine pathway activation extends C. elegans lifespan, suggesting modulation of ageing by endogenous molecules.
In a first step, I am exploring the mechanism by which hexosamine metabolites improve protein quality control in mammals, using cultured mammalian cells and a mouse model for neurodegeneration. Preliminary data show that hexosamine pathway metabolites enhance proteolytic capacity in cells and reduce protein aggregation, suggesting conservation. Second, I am investigating molecular mechanisms that activate the hexosamine pathway to promote protein homeostasis and counter ageing. Third, I am performing a direct forward genetic screen for modulators of ageing in C. elegans. For the first time, mutagenesis and next generation sequencing can be paired in forward genetic screens to interrogate the whole genome for lifespan-extending mutations in a truly unbiased manner. This innovative approach has the potential to reveal novel modulators of the ageing process.
Taken together, this work aims to understand molecular mechanisms that maintain cellular homeostasis to slow the ageing process, and to develop a new technology to identify yet unknown genetic modulators of ageing.
Conclusion of the Action:
1. I have investigated how the hexosamine pathway modulates cellular protein quality control in mammalian cells. Our published work (Horn et al., 2020 iScience) shows that hexosamine pathway activation is a trigger for a conserved stress response pathway, the integrated stress response (ISR). A mild ISR activation that we observed both in C. elegans and in mammalian cells, activated autophagy that was required to clear toxic protein aggregates.
2. Through biochemical and structural biology approaches we have delineated the molecular regulatory mechanism of GFAT-1 the key enzyme of the hexosamine pathway (Ruegenberg et al., 2020 Nature Commun).
3. We expanded, beyond the initial scope of the project, our research to genetic screens in haploid cells which enable high-resolution mechanistical insights in to protein function (Horn et al., 2018 Oncotarget; Allmeroth et al., 2020 Leukemia). This work has also revealed new insights into the regulation of the hexosamine pathway.
4. We performed a forward longevity screen in C. elegans, as outlined in the initial proposal, and have now identified many new longevity loci, one of which revealed a new function of the ISR in longevity (Derisbourg et al., 2020 bioRxiv)
