The group elucidated how oxidative stress affects senescence in human endothelial cells and dermal fibroblasts. We found that during senescence, key metabolic pathways for ATP production—oxidative phosphorylation, glycolysis, and glutaminolysis—are impaired. We also identified Nox4 as crucial for induction of senescence in human endothelial cells, involving mitochondrial dysfunction and nuclear DNA damage. Additionally, endonuclease G and FAHD1 were found to regulate cellular senescence and survival. In the case of FAHD1, the first oxaloacetate 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.
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 essential roles of autophagy and mitophagy for the survival of senescent fibroblasts, establishing NIX-dependent mitophagy as an indispensable mechanism UVB-induced senescence of fibroblasts. Our studies with melanocytes revealed distinct evolutionary mechanisms involved in senescence of skin cells localized in different skin compartments by showing that melanocytes are more resistant to UVB irradiation in comparison to fibroblasts. Additionally, we explore the SASP composition of senescent cells and have demonstrated that secreted molecules such as GDF15, CLCA2 as well as extracellular vesicles containing mitochondria play an important role in cellular senescence and skin homeostasis.

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