Zhou Yiming, Chen Lijuan, Wang Meijing, Yang Yang, Hu Bin, Li Guolin, Wei Fang
Center for Aging Biomedicine, College of Life Sciences, National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, Hunan Normal University, 36 Lushan Road, Changsha, 410081, Hunan, China.
Key Laboratory of Hunan Province for Model Animal and Stem Cell Biology, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
Geroscience. 2024 Dec 27. doi: 10.1007/s11357-024-01492-7.
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.
帕罗西汀是一种选择性5-羟色胺再摄取抑制剂，广泛应用于抑郁症的临床治疗。虽然几种抗抑郁药显示出作为老年保护剂的前景，但帕罗西汀在衰老过程中的作用仍不清楚。在本研究中，我们评估了帕罗西汀对线虫寿命的延长作用，并阐明了其潜在机制。结果表明，帕罗西汀可以延长线虫的寿命，同时伴随着健康寿命的延长，表现为活动能力增强和脂褐素积累减少，并且能使线虫对不同的非生物应激具有保护作用。帕罗西汀上调ser-7的表达，下调dop-4的表达。dop-4 RNA干扰（RNAi）模拟了帕罗西汀对寿命的有益作用。相反，ser-7 RNAi消除了帕罗西汀诱导的寿命延长以及dop-4和胰岛素/胰岛素样生长因子1信号通路（IIS）相关基因的表达变化。此外，帕罗西汀表现出与daf-2或age-1突变体相当的寿命延长作用；然而，这种作用在daf-16突变体中被消除。综上所述，这些结果表明帕罗西汀通过ser-7-dop-4-IIS途径促进线虫的健康和长寿，突出了其作为老年保护剂的潜力。
