Research Area 3: PTM-mediated alteration of signalling proteins

SP10  - Christian Hübner
Glycosylation of alpha-dystroglycan in the aging and diseased muscle

SP11 - Claudia Großmann
Non-enzymatic modifications of the mineralocorticoid receptor (MR) during vascular ageing 

 - Stefan H. Heinemann
Impact of methionine oxidation on rapid electrical signalling

 - Regine Heller
Mechanisms and consequences of age-related AMPK modification in endothelial cells

SP14 - Otmar Huber
 The role of glucose-induced Wnt/β-catenin signalling in ageing

Ageing is characterised by deregulated nutrient sensing. While anabolic signalling
such as the insulin-IGF pathway accelerates ageing, decreased nutrient signalling extends longevity. The latter is mediated by proteins that sense nutrient scarcity, explaining that dietary restriction increases lifespan or health span in eukaryote species, including nonhuman primates. In this context the already mentioned NAD+-dependent SIRT1 and AMPK are important anti-ageing molecules. AMPK activation has been shown to mediate lifespan extension in C. elegans and mice (Anisimov et al., 2011; Mair et al., 2011). It has multiple effects on metabolism including inhibition of mTORC1, which is activated via insulin, and is involved in positive feedback loops with SIRT1. Changes in cellular signalling do not only concern nutrient-triggered pathways but also inflammatory pathways including NF-B-induced signalling and inflammasome activation. Various other pathways may be affected by age-related alterations, especially because increased oxidative stress and hyperglycaemia, two conditions observed in aged organisms, are able to induce irreversible modifications of signalling proteins. Research Area 3 is constituted of projects dealing with age-related effects on modification of distinct signalling proteins or pathways with the aim to unravel previously unknown mechanisms of ageing and explore possible protective mechanisms. Most investigations will be performed using models of aged and young mice or cells prepared from these mice. The investigated PTMs will mainly include modifications induced by reactive oxygen or nitrogen species or by glucose metabolites. SP10 addresses the question whether ageing leads to PTMs of tight junction proteins in intestinal epithelial cells, especially after exposure of mice to a fructose-rich diet, and whether these modifications interfere with pathways of barrier stabilisation. Increased barrier permeability would allow translocation of bacterial endotoxins, which in turn would promote the development of a metabolic syndrome in aged individuals. SP11 has the aim to clarify whether oxidative PTMs of the mineralocorticoid receptor shift its signalling towards an inflammatory response, which may play a role in cardiovascular disease. In SP12 it will be investigated whether methionine oxidation of voltage-gated ion channels increases with age, possibly due to a decreased expression of methionine sulfoxide reductases, and whether this affects dorsal root ganglia-mediated electrical signalling, which contributes to functional alteration in ageing. The main focus of SP13 is to understand how age-related PTMs of AMPK may affect its anti-ageing function in endothelial cells and whether this is connected to cardiovascular ageing. Finally, SP14 will identify PTMs of the -catenin/Wnt-signalling as function of age and hyperglycaemia and explore their role in stress responses in ageing. The projects of Research Area 3 are highly relevant for understanding mechanisms of specific age-associated diseases (cardiovascular, metabolic) and pathologies (nociception). They also include targeting strategies to interfere with the observed eneration of PTMs (methionine sulfoxide reductases, antioxidants), which may open the way for preventive strategies. Furthermore, new analytical tools to analyse PTMs (SP12) and the characterisation of novel biomarkers (SP13) are expected.