State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Medical School, Southeast University, Nanjing, China.
State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing 211166, China.
Ecotoxicol Environ Saf. 2024 Oct 15;285:117136. doi: 10.1016/j.ecoenv.2024.117136. Epub 2024 Sep 30.
Bisphenol S (BPS) is widely presented and affects aging with unclear mechanisms. Here, we applied C. elegans to evaluate the effects of BPS on lifespan and healthspan and to investigate the underlying mechanisms. Both early-life and whole-life exposure to BPS at environmentally relevant doses (0.6, 6, 60 μg/L) significantly decreased lifespan, and healthspan (body bend, pharyngeal pumping, and lipofuscin accumulation). BPS exposure impaired mitochondrial structure and function, which promoted ROS production to induce oxidative stress. Furthermore, BPS increased expressions of the insulin/IGF-like signaling (IIS). Also, BPS inhibited expression of the IIS transcription factor daf-16 and its downstream anti-oxidative genes. Quercetin effectively improved BPS-induced oxidative stress byreversing BPS-regulated IIS/daf-16 pathway and anti-oxidative gene expressions. In daf-2 and daf-16 mutants, the effects of BPS and quercetin on lifespan, healthspan, oxidative stress, and anti-oxidative genes expressions were reversed, demonstrating the requirement of IIS/daf-16 for aging regulation. Molecular docking and molecular dynamics simulations confirmed the stable interaction between DAF-2 and BPS mainly via three residues (VAL1260, GLU1329, and MET1395), which was attenuated by quercetin. Our results highlighted that adverse effects of BPS on impairing lifespan and healthspan by affecting IIS/daf-16 function against mitochondrial stress, which could be inhibited by quercetin treatment. Thus, we first revealed the underlying mechanisms of BPS-induced aging and the potential treatment.
双酚 S（BPS）广泛存在并影响衰老，但具体机制尚不清楚。本研究应用秀丽隐杆线虫评估 BPS 对寿命和健康寿命的影响，并探讨其潜在机制。在环境相关剂量（0.6、6、60μg/L）下，早期和终生暴露于 BPS 均显著缩短寿命和健康寿命（体弯、咽泵和脂褐素积累）。BPS 暴露损害线粒体结构和功能，促进 ROS 产生诱导氧化应激。此外，BPS 增加胰岛素/IGF 样信号（IIS）的表达。BPS 还抑制 IIS 转录因子 daf-16 及其下游抗氧化基因的表达。槲皮素通过逆转 BPS 调节的 IIS/daf-16 途径和抗氧化基因表达，有效改善 BPS 诱导的氧化应激。在 daf-2 和 daf-16 突变体中，BPS 和槲皮素对寿命、健康寿命、氧化应激和抗氧化基因表达的影响被逆转，表明 IIS/daf-16 对衰老调控的必要性。分子对接和分子动力学模拟证实了 DAF-2 和 BPS 之间的稳定相互作用主要通过三个残基（VAL1260、GLU1329 和 MET1395），而槲皮素则减弱了这种相互作用。我们的研究结果强调，BPS 通过影响 IIS/daf-16 功能对抗线粒体应激，从而对寿命和健康寿命产生不利影响，而槲皮素治疗可以抑制这种影响。因此，我们首次揭示了 BPS 诱导衰老的潜在机制和治疗方法。
