Escitalopram accelerated aging via impaired IIS/autophagy signaling pathway.

Abstract

Escitalopram is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) for treating depression and anxiety disorders in adolescents and pregnant women. While some SSRIs have been reported to extend lifespan, the impact of escitalopram on the aging process remains unclear. Here, we demonstrated that escitalopram administration at juvenile, young, or old adult stages significantly shortens lifespan and impairs healthspan in Caenorhabditis elegans. This pro-aging phenotype was accompanied by increased lipofuscin accumulation and reduced stress resistance. Mechanistically, escitalopram induced mitochondrial dysfunction, characterized by elevated ROS production and diminished membrane potential. Genetic analyses established that these detrimental effects are mediated by the insulin/IGF-1 signaling (IIS) pathway, leading to the subsequent suppression of autophagy. Mutant worms in IIS (daf-2, daf-16, and sod-3) or autophagy-related genes (unc-51, atg-3, and atg-13) abolished the lifespan reduction. Consistently, in human BJ fibroblasts, escitalopram triggered premature cellular senescence, marked by increased SA-β-gal activity and upregulated P53/P21 expression, and impaired cell proliferation, which was mediated by impairment in fusion between autophagosome and lysosome. Collectively, our cross-species study reveals that escitalopram, contrary to some other SSRIs, accelerates aging through impairment of the evolutionarily conserved IIS/autophagy axis, suggesting its potential pro-aging toxicity with long-term use.