The correct function and tight regulation of protein synthesis are essential for organismal health. Cellular proteostasis is guaranteed by the balance between the synthesis of new proteins, their maintenance in a functional state by defence mechanisms and refolding, and the clearance of damaged proteins by autophagy or the ubiquitin-proteasome system. Accumulating evidence suggests that cellular senescence affects all levels of proteostasis. An additional layer of complexity is added by mitochondrial ribosomes contained in eukaryotic cells besides the ribosomes in the cytosol. Both types of ribosomes appear to be coordinated, and the balance between cytosolic and mitochondrial translation may be altered under stress, in senescent cells and by ER-mitochondrial contact sites.

As a central aim of this project area, we will characterize protein synthesis in the cytosol and the mitochondria in different senescence models.

Another goal of this project area is the identification of novel senotherapies. For this aim, we will screen pre-selected compounds in human cells for their senolytic and senomorphic potential. We will further test them in Caenorhabditis elegans for their effect on survival and healthspan. Moreover, we will conduct a small pilot study in mice.

After completing work in this project area, we will have identified senescence-related cytosolic and mitochondrial proteostasis mechanisms, potentially targetable by pharmacological interventions. Furthermore, we will have contributed low- to medium-throughput screens in human cells, nematodes, and mice to the overall aim of the SENIOPROM consortium to discover novel senotherapies.