Aging triggers physiological changes in organisms that are tightly linked to metabolic changes. Senolytics targeting many fundamental aging processes are currently being developed. However, the host metabolic response to natural senescence and the molecular mechanism underlying the antiaging benefits of senolytics remain poorly understood. In this study, we investigated metabolic changes during natural senescence based on the Caenorhabditis elegans model and pinpointed potential biomarkers linked to the benefits of senolytics. These results suggest that age-dependent metabolic changes during natural aging occur in C elegans. Betaine was identified as a crucial metabolite in the natural aging process. We explored the metabolic effects of aging interventions by administering 3 antiaging drugs—metformin, quercetin, and minocycline—to nematodes. Notably, betaine expression significantly increased under the 3 antiaging drug treatments. Our findings demonstrated that betaine supplementation extends lifespan, primarily through pathways associated with the forkhead box transcription factor (FoxO) signaling pathway, the p38-mitogen-activated protein kinase (MAPK) signaling pathway, autophagy, the longevity regulating pathway, and the target of rapamycin (mTOR) signaling pathway. In addition, autophagy and free radicals are altered in betaine-treated nematodes. Overall, we found that betaine is a critical metabolite during natural aging and that senolytics extend the lifespan of nematodes by increasing betaine levels and promoting autophagy and antioxidant activity. This finding suggests that betaine could be a novel therapeutic target for promoting longevity.

中文翻译：

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Senolytics 通过改变甜菜碱代谢来延长秀丽隐杆线虫的寿命


衰老会引发与代谢变化密切相关的生物体的生理变化。目前正在开发针对许多基本老化过程的 Senolytics。然而，宿主对自然衰老的代谢反应以及 senolytics 抗衰老益处背后的分子机制仍然知之甚少。在这项研究中，我们基于秀丽隐杆线虫模型调查了自然衰老过程中的代谢变化，并确定了与 senolytics 益处相关的潜在生物标志物。这些结果表明，自然衰老过程中的年龄依赖性代谢变化发生在秀丽隐杆线虫中。甜菜碱被确定为自然衰老过程中的关键代谢物。我们通过对线虫施用 3 种抗衰老药物——二甲双胍、槲皮素和米诺环素——来探索衰老干预的代谢影响。值得注意的是，甜菜碱表达在 3 种抗衰老药物治疗下显着增加。我们的研究结果表明，甜菜碱补充剂主要通过与叉头盒转录因子 （FoxO） 信号通路、p38-丝裂原活化蛋白激酶 （MAPK） 信号通路、自噬、长寿调节通路和雷帕霉素靶标 （mTOR） 信号通路相关的通路延长寿命。此外，甜菜碱处理的线虫中的自噬和自由基发生改变。总体而言，我们发现甜菜碱是自然衰老过程中的关键代谢物，并且 senolytics 通过增加甜菜碱水平和促进自噬和抗氧化活性来延长线虫的寿命。这一发现表明甜菜碱可能是促进长寿的新型治疗靶点。