Research Area 1: PTM‐mediated mechanisms of ageing

SP1 - Marcus A. Glomb
Analysis of novel advanced glycation end products – Mechanisms and significance to ageing and related pathologies

 - Rüdiger Horstkorte
The role of sialylation and O-GlcNAcylation in differentiation and ageing

 - Thorsten Pfirrmann
The role of protein glycation on proteostasis

 - K. Lenhard Rudolph
Signalling pathways regulating asymmetric segregation of damaged proteins in stem cells 

 - Barbara Seliger
Characterisation of age-related changes within the lysine acetylation pattern of immune effector cells

The major aim of Research Area 1  is to unravel the importance of different PTMs in the ageing process by analysing specific PTM patterns in cells and tissues and to relate them to alterations of cellular function and differentiation. All age-relevant PTMs addressed in this proposal, acetylation, glycosylation, glycation and oxidation, will be investigated with partial overlapping between different projects. From these studies the identification and characterisation of new proteins involved in the ageing process is expected. A number of ageing models will be applied including yeast, stem cells, transgenic mice models and human samples. Longitudinal studies in yeast and mice monitoring PTMs during chronological ageing as well as comparative investigations with young and aged mice or young and old healthy donors will be performed. Research Area 1 combines strong technical expertise with novel approaches to characterise new PTMs, to identify novel age-dependent metabolic sensors and pathways and to investigate the competition of different PTMs and their role in ageing processes. SP1 will focus on recently discovered amide-AGEs and their occurrence and function. New coupled HPLC-MS/MS methods for biological samples and collaborations with several other subprojects will be established. SP2 will characterise the role of two glycosylation processes, sialylation and O-GlcNAcylation, which are both strongly influenced by glucose abundance, in mice models of ageing. Importantly, sialic acid engineering will be applied to interfere with sialylation and to test its influence on
functional maintenance in cellular models. SP3 will investigate how glycation of metabolic enzymes affects degradability by the ubiquitin-proteasome system with the aim to unravel the mechanism behind proteolytic insufficiency observed in aged cells. In SP4, pathways underlying the asymmetry in the segregation of carbonylated proteins and AGEs in embryonic stem cells will be investigated. This process may be involved in stem cell renewal and prevent ageing. Finally, in SP5 the relationship between immunosenescence and acetylation patterns will be studied in lymphocyte subpopulations of young and old human donors and age-related changes will be identified. Findings from this human study can be immediately translated into the evaluation of potential biomarkers of ageing. From Research Area 1 we expect not only insights into the relationship of protein modification and processes relevant for ageing but also the identification of age-sensitive pathways and approaches to interfere with these pathways. Translational impact is expected from SP1 (analysis/diagnostics), SP2 (treatment strategies) and SP5 (biomarker analysis).