The group has elucidated the role of oxidative stress on senescence phenotypes of human endothelial cells and dermal fibroblasts. We found that upon entry into senescence, the major metabolic pathways required for ATP production, namely oxidative phosphorylation, glycolysis and glutaminolysis, are impaired in human fibroblasts and endothelial cells. Moreover, energy depletion achieved by various treatments induces premature senescence in such cells. These findings have led to the new hypothesis that the downregulation of cellular ATP regeneration systems is a major cause of cellular senescence. For senescence of human endothelial cells, a key role of  the NADPH oxidase Nox4 was established and we found that senescence  induction by Nox4 involves mitochondrial dysfunction and nuclear DNA damage. In addition, two mitochondrial proteins, endonuclease G and FAHD1, were identified which regulate cellular senescence and survival; studies of molecular mechanisms are underway. In the case of FAHD1, experiments in yeast, worms and flies suggest that FAHD1 is essential for the full lifespan of these organisms. Mouse and nematode models with FAHD1 gene deletion were established; their phenotypical characterization is underway. Genome-wide transcriptional profiling was used to identify a group of genes involved in premature  senescence caused by energy failure, and preliminary data suggest that regulation of autophagy plays an important role in this context. Using advanced proteomics methods as well as RNA profiling, we have established the secretome profiles of young and senescent human cells and validated several candidate genes by functional analysis. Besides extracellular IGF-binding proteins, which seem to play distinctive roles in the senescent phenotype of human fibroblasts and endothelial cells, we also found an important role for TL1A, a member of the tumor necrosis factor family, as a regulator of senescence and cell death in human endothelial cells.