Freitag, 26.09.2014

08:00 - 09:30 Uhr

Löwengebäude HS XIII

Vorsitz: Fuellen, Georg (Rostock); Bürkle, Alexander (Konstanz)

Wie Bioinformatik und Systembiologie Alternsprozesse beleuchten

"Was hat die computergestützte Analyse von Daten zu Alterungsprozessen bisher erbracht, und was ist zukünftig möglich?"

Unter dieser Leitfrage sollen exprimentell, klinisch und theoretisch orientierte Kolleginnen und Kollegen einen Überblick erhalten zu computergestützten Ansätzen. Dabei reicht das Spektrum von den Erkenntnismöglichkeiten zu grundsätzlichen Fragen zur Biologie des Alterns bis hin zur Stratifizierung bzw. Individualisierung von Diagnose und Therapie.

Die computergestützte Analyse von Daten zu Alterungsprozssen mit Hilfe der Bioinformatik, Systembiologie/Systemmedizin und Biostatistik soll anhand von Projekten beleuchtet werden, die u.a. vom BMBF im Rahmen der 'GerontoSys'- Initiative gefördert wurden. Beispiele sind die Alterung von Fibrobasten der Haut, die Alterung von Stammzellen, und Biomarker der Alterung im Blutbild.

Aufbauend auf diesen Beispielen und einer Darstellung künftig anfallender Daten soll in der Diskussion der Blick in die Zukunft gerichtet werden.

Welche (longitudinalen) Daten aus Kohortenstudien und von Modellorganismen sind in Zukunft zu erwarten?
Was erwarten Firmen wie Calico (ein Spinoff von Google) und Human Longevity Inc. (eine Gründung von Craig Venter) an Erkenntnissen?
Was können wir lernen über die Biologie der Alterungsprozesse?
Welche Art von Empfehlungen für den Einzelnen sind zu erwarten?
Welche Erkenntnisse können hilfreich sein für Gerontologen und Geriater?

08:00 Uhr

A. Bürkle
Molekulare Toxologie, Fachbereich Biologie, Universität Konstanz, Konstanz;

S101-01

Die Messung biologischen Alters beim Menschen: Resultate des EU-FP7-Projektes MARK-AGE

Measurement of biological age in humans: Results from the EU FP7 MARK-AGE project
(Vortrag auf Deutsch)

The rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Age-related changes in body function or composition that could serve as a measure of “biological” age and predict the onset of age-related diseases and/or residual lifetime are termed “biomarkers of ageing”. Many candidate biomarkers have been proposed but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has so far proven to yield a useful biomarker of ageing on its own, probably due to the multi-causal and multi-system nature of ageing.
The MARK-AGE Consortium (www.mark-age.eu), comprising 26 partners from 14 European countries, has therefore conducted a population study (3,300 subjects) aiming at the identification of a set of biomarkers of ageing that could serve as a measure of biological age.
Two larger groups of subjects have been recruited, i.e. (i) randomly recruited age-stratified individuals from the general population covering the age range 35-74 years and (ii) subjects born from a long-living parent belonging to a family with long living sibling(s) already recruited in the framework of the GEHA project. For genetic reasons such individuals (termed GEHA offspring) are expected to age at a slower rate. They have been recruited together with their spouses as controls, thus allowing initial validation of the biomarkers identified. (iii) A small number of patients with progeroid syndromes have also included in the study. A wide range of candidate biomarkers were tested, including (a) classical ones for which data from several smaller studies have been published; (b) new ones, based on recent preliminary data, as well as (c) novel ones, based on recent research on mechanistic aspects of ageing, conducted by project participants. Bioinformatic analyses have been performed to extract a robust set of biomarkers of human ageing from the large amounts of data generated.
Data on the top 10 biomarkers will be shown. Based on our results we have developed a strategy to determine biological age of men and women, respectively, which also will be shown.

08:15 Uhr

F. Boege
Zentralinstitut für Klinische Chemie und Laboratoriumsdiagnostik, Heinrich Heine Universität Düsseldorf, Düsseldorf;

S101-02

Unzureichende mitochondriale Biogenese in primären Hautfibroblasten alter Menschen ist verbunden mit einer Beeeinträchtigung der PGC1A-unabhängigen Stimulation

Inadequate mito-biogenesis in primary dermal fibroblasts from old humans is associated with impairment of PGC1A-independent stimulation
(Vortrag auf Deutsch)

Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, which may be a cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20 - 67 years and analysed ex vivo at low population doubling precluding replicative senescence. According to gene set enrichment analysis of genome wide array data, the most prominent age-associated change of the transcriptome was decreased expression of mitochondrial genes. Consistent with that, mitochondrial content and cell proliferation declined with donor age. This was associated with upregulation of AMP-dependent protein kinase (AMPK), increased mRNA levels of PPAR?-coactivator 1a (PGC1A) and decreased levels of NAD+-dependent deacetylase sirtuin 1. In the old cells the PGC1A-mediated mito-biogenetic response to direct AMPK-stimulation by AICAR was undiminished, while the PGC1A-independent mito-biogenetic response to starvation was attenuated and accompanied by increased ROS-production. In summary, these observations suggest an age-associated decline in PGC1A-independent mito-biogenesis, which is insufficiently compensated by upregulation of the AMPK/PGC1A-axis leading under base line conditions to decreased mitochondrial content and reductive overload of residual respiratory capacity.

Kalfalah et al. Exp Gerontol, in press, http://dx.doi.org/10.1016/j.exger.2014.03.017

08:30 Uhr

S. Schuster
Department of Bioinformatics, Friedrich Schiller University Jena, Jena;

S101-04

Computersimulation des Stoffwechsels im Rahmen der Alternsforschung

Computer simulation of metabolism in the framework of age research

Numerous metabolic processes are linked with ageing. Due to their complexity, computer simulation can help us enormously to understand the effects of changes in metabolism and even to predict hitherto unknown phenomena.
In this talk, I demonstrate the use of computer simulation by two examples. The first concerns nicotinamide adenine dinucleotide (NAD+), which is well known as a crucial cofactor in the redox balance of metabolism. Moreover, NAD+ is degraded in ADP-ribosyl transfer reactions which are important components of multitudinous signalling reactions. These include reactions linked to DNA repair and ageing. Proteins are modified by mono-ADP-ribosylation and poly-ADP-ribosylation. Histones are subject to NAD+-dependent deacetylation catalyzed by SIRTUINs, which have been shown to increase lifespan in a number of species. Several hypotheses on the relation of calorie restriction to NAD+ metabolism have been put forward.
Using the concept of elementary flux modes (EFMs), we determined all potential routes in a network describing NAD+ biosynthesis and degradation. All known biosynthetic pathways, which include de novo synthesis starting from tryptophan as well as the classical Preiss-Handler pathway and NAD+ synthesis from other vitamin precursors, are detected as EFMs. Moreover, several elementary modes are found that degrade NAD+, represent futile cycles or have other functionalities. A phylogenetic analysis of NAD metabolism in 45 species was performed, which documents significant differences between species. We critically examine the hypothesis that calorie restriction increases NAD+ turnover without altering steady-state NAD+ levels.
The second example concerns the detection of futile cycles in a genome-scale human metabolic network. While it is, so far, impossible to detect all of them due to combinatorial explosion, a representative sampling can be performed. Our analysis did not reveal any significant increase or decrease in futile cycling during ageing.

08:45 Uhr

G. Fuellen
Institut für Biostatistik und Informatik in Medizin und Alternsforschung, Universitätsmedizin Rostock, Rostock;

S101-05

Daten zu Alterungsprozessen: Analysestrategien von gestern und Herausforderungen von morgen

Im ersten Teil des Vortrags soll dargestellt werden, welche spezifischen Beiträge computergestützte Analysen bisher geliefert haben für das Verständnis von Alternsprozessen, mit einem Schwerpunkt auf longitudinalen Daten. Methoden und Ergebnisse werden vorgestellt. Hier sollen u.a. Genexpressionsdaten und Blutbildmarker als Beispiele dienen (Moeller et al, Aging Cell, in press.)

Im zweiten Teil des Vortrags geht es um zukünftige Analysen:
Wie können Kohortenstudien beim Menschen und entsprechende Studien bei Modellorganismen gestaltet werden, um maximalen Erkenntnisgewinn zur Biologie von Alternsprozessen und zur Frage nach validierten Interventionsstrategien zur Verlangsamung von Alternsprozessen zu ermöglichen? Hierzu soll insbesondere fünf Fragen nachgegangen werden: Wie kann der Schwerpunkt auf die Maximierung der 'Healthspan' (der Lebensspanne ohne schwerwiegende chronische Erkrankungen) gelegt werden? Wie kann der zusätzliche Nutzen der Ergebnisse für die Fitness älterer Arbeitnehmer und potentieller geriatrischer Patienten erhöht werden?
Wie wichtig sind individualisierte bzw. stratifizierte Ansätze?
Welche Analysestrategien sind für welche Studienkonzepte erforderlich, bzw. welche müssen neu entwickelt werden?
Wann helfen Hochdurchsatzdaten (z.B. Genomdaten und Genexpressionsdaten), wann helfen detaillierte Modelle (z.B. von Signalwegen) ?

09:00 Uhr

Diskussion

 

Alle Vorträge werden auf Deutsch gehalten