SeMoVi - 140307 Bohmann Keime Fanchon — BioSyL - Réseau de Biologie Systémique de l'Université de Lyon

14h00 - 15h00	Dirk Bohmann, University of Rochester Medical Center Stress, Metabolism, and the Control of Longevity More information on the Dirk Bohmann's website
15h00 - 15h30	Pause café
15h30 - 16h30	Céline Keime, PRABI Comparative transcriptomic analysis for the study of self-renewal Eric Fanchon, TIMC-IMAG, Grenoble Using discrete abstractions to model the dynamics of biological networks
16h30 - 17h00	Discussion générale

Dirk Bohmann, University of Rochester Medical Center
Stress, Metabolism, and the Control of Longevity

Research conducted over the last decade has raised considerable interest in the mechanisms underlying aging and senescence. Particularly experiments in simple model organisms, such as yeast, C. elegans and Drosophila, have led to the suggestion that aging is not, as was widely presumed previously, the result of inevitable degeneration, but a regulated process. Thus, aging research aims at understanding and ultimately manipulating the genetic mechanisms controlling aging and longevity. Two major aspects of cell function appear as especially relevant in this regard: mechanisms that defend against oxidative damage and metabolic control.

The oxidative stress theory of aging predicts that bolstering the organisms anti-oxidant defenses may retard the aging process and extend lifespan. This hypothesis has received considerable support in recent years, mainly by studies in model organisms showing that genetic manipulation of anti-oxidant genes can augment oxidative stress tolerance and promote longevity. By extension, the signaling pathways that regulate anti-oxidant responses are plausible regulators of the aging process. We have tested this notion using Drosophila genetics, concentrating initially on the stress inducible JNK signal transduction pathway. Our work has shown that JNK signaling defends Drosophila against acute oxidative stress, delays the accumulation of oxidative damage throughout life, and extends lifespan, without affecting development or reproduction. Interestingly, in the context of aging regulation, JNK acts by activating the transcription factor Foxo. Foxo had previously been shown to be down-regulated by insulin signaling and be required for life extending effects of decreased insulin signaling that has been observed in several model organisms. One conclusion of our experiments is that JNK and insulin signaling antagonize each other in the regulation of lifespan.

Recently we demonstrated that signaling that activates the Drosophila homologue of the Nrf-2 transcription factor has a similar function as JNK in the regulation of lifespan. Nrf2 (NF-E2-Related Factor 2) and its cytoplasmic inhibitor Keap1 (Kelch-like ECH-Associated Protein 1) regulate the basal and oxidative stress-induced activity of many anti-oxidant genes and detoxification enzymes. Furthermore, Nrf-2 activation has been found to have cancer preventive functions.

Our studies demonstrate that oxidative stress and metabolic signals engage a complex signaling machinery that influences aging and senescence, but might also be relevant for a number of other maladies including cancer and diabetes.

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SeMoVi - 140307 Bohmann Keime Fanchon