Novel Approaches To Eliminate Senescent Cells For The Amelioration Of Age-Related Diseases

Ageing is characterized by a gradual decline in tissues and organs' functions, which leads to death over time. The accumulation of senescent cells in different organs is one of the main hallmarks of ageing, resulting in age-related diseases, including neurodegenerative disorders, idiopathic pulmonary fibrosis, skin ageing and cancer. Consistent with this, studies have revealed that eliminating senescent cells reduces their negative impact on tissue homeostasis and enhances physical health and lifespan in animals. However, current methods of targeting and eradicating senescent cells lack specificity and have off-target consequences due to a lack of unique, universal biomarkers capable of identifying senescent cells. Here, we investigated four potential novel markers of senescence, LANCL1, STX4, MYO1B and SNX9, which were recently identified in a screen of proteins increased in senescent cells, but results were inconclusive. Moreover, we tested novel approaches to target and eliminate senescent cells. First, we used senoblocking, a strategy for preventing the development of senescence before it occurs. For that purpose, we treated a progeroid mouse model with Ibrutinib, a clinically available BTK inhibitor. BTK inhibition has previously been shown to prevent cellular senescence. Our results show that Ibrutinib improves healthspan, extends lifespan, improves skin ageing-related changes and alleviates age-related lung fibrosis by reducing the accumulation of senescent cells. Second, given the involvement of HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Taken together, the results from our research show that Ibrutinib and CUDC-907 are novel promising therapeutic interventions for the elimination of senescent, which could be exploited clinically in future.