Strategies to target senescence

Cellular senescence is a complex stress response playing a causal role in many age-related pathologies. Promising strategies aimed at clearing senescent cells are potentially able to slow down the ageing process. To identify novel senolytic compounds, we have screened libraries comprising ~2,000 small molecules using systems of oncogene-induced and therapy-induced senescence. We have assessed the senolytic effect of these compounds in different cell types and in response to different senescent inducers. Interestingly, we observed that while some compounds have just selectivity to kill cells undergoing oncogene-induced senescence, others behaved as broad-spectrum senolytics. Here, we will show our progress on validation of one of these small molecules that displays conserved senolytic activity across different senescence models. So far, our results suggest the on-target activity of this compound and members of its family. Additional experiments are being conducted to gain mechanistic insights into the underlying signaling pathways involved. Moreover, preliminary results show the ability of this compound to selectively kill senescent cells in vivo in the context of natural ageing, therapy-induced senescence, and oncogene-induced senescence. Overall, our results suggest drug screens are a useful tool to identify new vulnerabilities of senescent cells and highlight the broad potential of senolysis as a therapeutic strategy.

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Anastasios Mastroskolias
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