Paroxetine promotes longevity via ser-7-dop-4-IIS axis in Caenorhabditis elegans

Paroxetine, a selective serotonin reuptake inhibitor, is widely used in the clinical treatment of depression. While several antidepressants show promise as geroprotectors, the role of paroxetine in aging remains unclear. In this study, we evaluated the lifespan extension effect of paroxetine in Caenorhabditis elegans (C. elegans) and elucidated the underlying mechanisms. The results showed that paroxetine can prolong lifespan concomitant extension of healthspan as indicated by increasing mobility and reducing lipofuscin accumulation, as well as confer protection to nematodes against different abiotic stresses. Paroxetine upregulated ser-7 expression and downregulated dop-4 expression. dop-4 RNA interference (RNAi) mimicked the beneficial effect of paroxetine on lifespan. Conversely, ser-7 RNAi abolished paroxetine-induced lifespan extension and the expression changes of dop-4 and genes related to insulin/insulin-like growth factor 1 signaling (IIS). Moreover, paroxetine exhibited a comparable lifespan extension effect to that observed in daf-2 or age-1 mutants; however, this effect was abolished in daf-16 mutant. Taken together, these results suggest that paroxetine promotes health and longevity in C. elegans through the ser-7-dop-4-IIS pathway, underscoring its potential as a geroprotector.