Invited webinar -Senolytics to eliminate senescent cells: promising strategy to...- by Dr. Johannes Grillari Evercyte

"Senolytics to eliminate senescent cells: promising strategy to improve tissue regeneration" presented by Dr. Johannes Grillari Evercyte, Ludwig Boltzmann Institute for Traumatology. The Research Center in Cooperation with AUVA, VIenna, Austria; Institute of Molecular Biotechnology, BOKU University, Vienna, Austria; Chaired by Prof. Anna Teti, DISCAB, University of L’Aquila.

With age, senescent cells accumulate in various tissues, which is causatively linked to a state of low-grade chronic inflammation, aging and age-related diseases. As a possible therapy for age-related diseases, the pharmacological ablation of senescent cells using senolytics was proven to be efficient in numerous preclinical disease models and first clinical pilot studies are ongoing. The herein used first generation senolytics, targeting senescent cell anti-apoptotic pathways (SCAPs), are mainly repurposed drugs that lack efficacy, selectivity and often have an unfavorable safety profile. Recently, we discovered an alternative target pathway for the development of novel senolytic compounds that is based on an altered lipid metabolism in senescent cells. We found that the enzymatic phospholipase A2 activity as well as the resulting metabolite arachidonic acid are significantly upregulated intracellularly in senescent cells. Since high levels of arachidonic acid can induce apoptosis, we tested, if inhibition of enzymes that use arachidonic acid as a substrate would increase its levels further to cytotoxic dosis specifically in senescent cells. Indeed, a range of various cell types were selectively eliminated in vitro when senescent. In vivo, the treatment of 26 months old C57BL6 mice resulted in decreased mRNA levels of p21 and SAbetaGal staining in various tissues as well as markedly improved neuromuscular functionality, frailty index score, as well as an around 40% increase in life span starting from treatment at the age of 27 months. In addition, we identified circulating miRNAs in plasma of mice that correlate with tissue levels of senescence marker genes in order to establish a companion diagnostic to monitor the senescent cell load. In summary, we here provide a promising novel strategy to assess the senescent cell load based on circulating miRNAs and then to eliminate senescent cells for counteracting functional decline and diseases associated with aging targeting the arachidonic acid metabolism.

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