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Background Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous condition associated with accelerated lung ageing. Lifestyle factors such as smoking increase oxidative stress driving emphysema, chronic bronchitis and small airway disease. In COPD, small airway epithelial cells show increased cellular senescence with increased expression of cell-cycle inhibitors p21CIP1 and p16INK4A and downregulation of the anti-ageing protein sirtuin (SIRT). 1 Cellular senescence describes irreversible cell cycle arrest with a senescence-associated secretory phenotype (SASP) involving inflammatory markers such as CXCL8 and senescence-associated β-galactosidase (SA-β gal). Fisetin is a flavonoid with senolytic properties but has limited efficacy due to rapid metabolism and low bioavailability. Geraldol, a methylated metabolite of fisetin, displays improved in-vivo retention. This study compares the efficacy of fisetin and geraldol in a BEAS-2B airway epithelial model of cellular senescence.Methods BEAS-2B cells were cultured with 50nM Doxorubicin on Day 0 and Day 2 to induce cellular senescence. 1 On Day 6, cells were treated 48 hours with 1–30 μM of fisetin, or geraldol. Cells were harvested on Day 8 for cell viability assays, SA-β-galactosidase, western blots and RT-qPCR measurements of p21CIP1, p16INK4A and SIRT1. CXCL8 secretion was quantified using ELISA.Results 50nM Doxorubicin-induced senescence in BEAS-2B cells demonstrated by increased p21CIP1 expression (p<0.05) and SA-β gal activity (n=7). When these cells were cultured with 10μM geraldol, there was a reduction in p21CIP1, p16INK4A and SIRT1 mRNA (p<0.05) (n=6). At 30μM, geraldol reduced SA-β-galactosidase activity and CXCL8 release by ~56% and ~59% respectively (p<0.01) along with a concentration-dependant reduction in p16INK4A, p21CIP1 and SIRT1 proteins (n=3). In contrast, fisetin showed no significant effects on any senescence marker examined.Discussion This study showed that geraldol was more effective than fisetin in reducing markers of doxorubicin-induced senescence in BEAS-2B cells.Conclusion These data suggest that geraldol could be a novel senotherapy for the treatment of COPD or other accelerated ageing conditions. Future directions should explore anti-apoptotic pathways, optimise harvest timings and use primary airway epithelial cells from COPD patients.Reference Generating senescent airway epithelial cell populations using low-concentration doxorubicin or etoposide. European Respiratory Journal 2021;58(suppl 65):PA3687. 10.1183/13993003.congress-2021.PA3687