Mittwoch, 24.09.2014

11:00 - 12:30 Uhr

Löwengebäude HS XIII

Vorsitz: Grillari, Johannes (Wien/A); Simm, Andreas (Halle (Saale))

Mechanisms of Aging and Stress Responses

Aging is mainly based on a life-long accumulation of molecular damage within molecules, cells and tissues. At some stages, the aggrieved molecules like for example mutated DNA, oxidized lipids or glycated proteins will lead to reduced cell and organ function and at the end to diseases. The accumulation of damage seems to be responsible for the reduction in organ function, especially the functional reserve, which is needed when the organ is stressed. All living systems have the ability to respond, to counteract and to adapt to the external and internal stress. A wide range of molecular, cellular and physiological pathways of repair are well known, and these range from nuclear and mitochondrial DNA repair to free radical counteracting mechanisms, protein turnover and repair, detoxification mechanisms, and other processes including immune response and further stress responses. Whereas high doses of stress can induce cell senescence and cell death, single or multiple exposure to low doses of otherwise harmful agents have a variety of anti-aging / hormetic effects.

The symposium will show how aging can impact the ability of cells, tissues or organisms to respond adequate to stress, signal pathways involved and possibilities to regulate these pathways are demonstrated.

11:00 Uhr

J. Grillari; S. Weilner1; M. Hackl2; E. Schraml; H. Redl; M. Schosserer; H. Dellago; R. Monteforte; M. Wieser1; R. Grillari
Department für Biotechnologie, Universität für Bodenkultur Wien, 1 Evercyte GmbH, 2 Tamirna GmbH, Wien/A;

S103-01

Novel modulators of the cellular and organismal life span: the stress connection

Cellular senescence has evolved from an in vitro model system to study aging to a multifaceted phenomenon of in vivo importance since senescent cells in vivo have been identified and their removal delays the onset of age-associated diseases in a mouse model system. In order to understand how senescent cells that accumulate within organisms with age negatively impact on organ and tissue function, we have started to characterize RNAs and proteins that are differentially expressed in early passage versus senescent cells. Besides the functional characterization of proteins, we have now focused on the large emerging class of non-coding RNAs, especially on miRNAs that only recently have been functionally implied in the regulatory networks that are modified during the aging process. Here we summarize examples of miRNAs but also proteins that have been identified as differentially regulated in senescent cells and on how they impact on the organismal healthspan, how they might be used as biomarkers of aging and how they are involved in the cellular and organismal stress response.

11:20 Uhr

B. Schreier; S. Rabe; S. Mildenberger; M. Hünerberg; D. Bethmann; M. Gekle
Julius-Bernstein-Institut für Physiologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale);

S103-02

Longterm inactivation of EGFR in vascular smooth muscle cells alters cardiovascular changes from early to late adulthood.

The epidermal growth factor receptor (EGFR) regulates e.g. cell proliferation, survival and differentiation leading for example to vascular dysfunction and remodeling, also during aging. In addition to activation by its classiclal ligands, EGFR is also subject to activation by e.g. angiotensin II - a mechanism called transactivation.
We generated a mouse model with a specific, inducible deletion of the EGFR in vascular smooth muscle cells (VSMC) and studied the influence of VSMC-EGFR on blood pressure in young adult animals (4 months) and older (10 months) animals. Systolic, diastolic and mean blood pressure were reduced in young knockout mice compared to wildtype, while there was no significant difference in blood pressure between the two genotypes in older animals. Upon angiotensin II infusion, maximum blood pressure increase as well as the area under the curve were reduced in young knockout animals. In contrast, in older animals maximum blood pressure increase was reduced in both genotypes, while the duration of blood pressure increase and the area under the curve were reduced in knockout compared to wildtype.
Taken together the presented data indicate, that the EGFR in VSMC is necessary for physiological blood pressure homeostasis and vascular angiotensin II action.

11:40 Uhr

N. Hartmann; C. Englert
Molecular Genetics Group, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena;

S103-03

Mitochondria and mild stress during ageing

Mitochondria have been implicated in the ageing process for several decades. In humans, decreased mitochondrial function has been described in patients with typical age-related diseases such as sarcopenia or neurodegenerative disorders. One strategy to combat mitochondrial dysfunction is to increase mitochondrial activity. Another approach could be to induce mild stress, because the concept of mitochondrial hormesis suggests that mild stress within the mitochondria causes an adaptive response that culminates in increased stress resistance and mitochondrial function. Within the Jena Centre for Systems Biology of Ageing (JenAge) we address the question how mild stress, mitochondria and ageing are connected.

For this purpose our group uses two fish species, the common laboratory model zebrafish Danio rerio and the extremely short-lived killifish Nothobranchius furzeri. We could show that ageing in N. furzeri is associated with changes of mitochondrial function and mitochondrial DNA. We observed that the mtDNA content and the amount of respiratory chain complexes III and IV decline with age in several organs. We found that mitochondrial respiration and ATP content are significantly reduced with age in skeletal muscle indicating a decline of mitochondrial function. Using a swim tunnel we could also show that the maximum swimming speed of N. furzeri significantly declines with age.

At the moment we study the effect of physical exercise on gene expression in both zebrafish and killifish at young and old age using next-generation sequencing of cDNA transcripts (RNAseq). Moreover, we treat young and old fish with low doses of rotenone, which blocks respiratory chain complex I, to induce mild stress in mitochondria. We are currently analysing the gene expression profiles after those perturbations and compare them with gene expression changes during normal ageing. In another approach, we have generated transgenic killifish lines that over-express Tfam and Pgc-1a, which both increase mitochondrial biogenesis in mammals. Overall, our findings suggest that despite the short lifespan, ageing in the killifish N. furzeri is associated with an impairment of mitochondrial function and with a decline in physical performance.

12:00 Uhr

R. Horstkorte; W. Weidemann; F. Hanisch1; S. Zierz1
Institut für Physiologische Chemie, Medizinische Fakultät, Martin-Luther Universität, 1 Universitätsklinik und Poliklinik für Neurologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale);

S103-04

Sialylation and muscle performance: Sialic acid is a marker of muscle ageing

Sialic acids are widely expressed as terminal monosaccharides on eukaryotic glycoconjugates. They are involved in many cellular functions, such as cell-cell interaction and signal recognition. The key enzyme of sialic acid biosynthesis is the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), which catalyses the first two steps of sialic acid biosynthesis in the cytosol. In this study we analysed sialylation of muscles in wild type and heterozygous GNE-deficient mice. We found that C57Bl/6 GNE+/- mice showed a significantly lower performance in the initial weeks of a treadmill stress compared to wild type C57Bl/6 GNE+/+animals. When analysing the membrane bound sialylation of C57Bl/6 GNE+/- mice in comparison to C57Bl/6 GNE+/+mice, levels of sialic acid were reduced by 33-53% at week 24 and by 12-15% at week 80. Interestingly, membrane bound sialic acid concentration increased with age of the mice by 16-46% in C57Bl/6 GNE+/+, but by 87-207% in C57Bl/6 GNE+/-.