Major Achievements

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. In the case of FAHD1, the first oxaloacetzate decarboxylase identified in eukaryotes, 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. 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.

We have additionally established different models to induce senescence in dermal fibroblasts and epidermal melanocytes with the aim to investigate the role of these senescent cells and their respective secretome in skin aging and disease. For instance, we have determined an essential role of autophagy for the survival of senescent fibroblasts and demonstrated a mechanism induced by impairment of the proteasome and dependence of ROS signaling for the establishment of the senescence phenotype when using UVB as a senescent inducer. In melanocytes we have highlighted the distinct evolutionary mechanisms involved in senescence of skin cells localized in different skin compartments by showing that the UVB dose necessary to induce senescence in melanocytes is almost four times higher than the one necessary for inducing senescence in fibroblasts. Furthermore, we have also demonstrated a key role of SASP factors secreted by senescent fibroblasts in the process of skin pigmentation. We also study the influence of other exposome factors on senescence in skin fibroblasts and extrinsic skin aging, using full thickness skin equivalents. More recent data highlight the role of protein and mitochondria quality control in extrinsic skin aging. We found that the presumptive mitokine GDF15 is required to limit mitochondrial dysfunction in late passage fibroblasts and that skin equivalents containing GDF15-deficient fibroblasts display age-related phenotypes, suggesting that such fibroblasts provide signals that influence keratinocyte homeostasis in the epidermis

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